Indole derivatives as 5-HT1-like agonists for use in migraine

ABSTRACT

The present invention relates to 3,5-disubstituted indole compounds which are selective agonists which act on 5-hdroxytryptamine receptors useful in the treatment of migraine.

This applicaiton is a 371 of PCT/EP 94/01121 filed Apr. 11, 1994.

The present invention relates to indole derivatives which act on5-hydroxytryptamine (5-HT) receptors.

More particularly the present invention relates to 3,5-disubstitutedindoles which are selective agonists at the "5-HT₁ -like" subtype of the5-hydroxytryptamine receptor. Such "5-HT₁ -like" receptors are presentin the carotid vascular bed and their activation causes vasoconstrictionwith a consequent reduction in carotid blood flow. Compounds which have"5-HT₁ -like" agonist activity are therefore useful in the treatment ofmedical conditions which are thought to result from excessive dilationof the carotid bed, such as migraine, cluster headache, chronicparoxysmal hemicrania and headache associated with vascular disorders.Certain compounds of the present invention are also agonists at central5-HT₁ receptors and are therefore useful for the treatment ofdepression, anxiety, eating disorders, obesity, drug abuse and emesis.

WO-A-92/06973 discloses a series of 3,5-disubstituted indoles havingutilities similar to those of the present invention and which arerelated to compounds of formula (IA), vide infra, but which containstructurally distinct 5-substitutents.

J. Med. Chem., 1963, 6, 719 relates, inter alia, to the synthesis, andantiserotonin and hypotensive properties, of certain 5-acyltryptamines,whilst J. Med. Chem., 1979, 22, 428 reports the serotonin receptorbinding affinities of various tryptamine analogues. In addition, theeffects of some tryptamine analogues on brain monoamines are describedin Neuropharmacology, 1972, 11, 373 (Chem. Abs., 1972, 77, 83394v).

The present invention provides compounds of formula: ##STR1##pharmaceutically acceptable salts thereof, and pharmaceuticallyacceptable-solvates (including hydrates) of either entity, wherein R¹ is##STR2## or CH₂ CH₂ NR³ R⁴ (E);

R² is R⁵ R⁶ C(OH)A or R⁷ COA;

R³ is H; C₁ -C₆ alkyl; (R⁸ CO) C₁ -C₃ alkylene; (R⁹ O₂ C) C₁ -C₃alkylene; (R¹⁰ R¹¹ NOC) C₁ -C₆ alkylene; (R¹⁰ R¹¹ NO₂ S) C₁ -C₃alkylene; [R⁸ S(O)_(m) ]C₁ -C₃ alkylene; (R¹² O) C₂ -C₄ alkylene; (R¹³NH) C₂ -C₄ alkylene; (C₃ -C₇ cycloalkyl) C₁ -C₃ alkylene; (aryl) C₁ -C₃alkylene; (heteroaryl) C₁ -C₃ alkylene; C₃ -C₇ cycloalkyl optionallysubstituted with HO; C₃ -C₆ alkenyl optionally substituted with aryl; C₅-C₇ cycloalkenyl; or C₃ -C₆ alkynyl;

R⁴ is H or C₁ -C₆ alkyl;

R⁵ and R⁶ are each independently selected from H; C₁ -C₆ alkyl; C₁ -C₄perfluoroalkyl; and C₃ -C₇ cycloalkyl; or, together with the carbon atomto which they are attached, form a 3- to 7-membered carbocyclic ringwhich optionally incorporates a double bond or a heteroatom linkageselected from O, S(O)_(m), NH, N(C₁ -C₄ alkyl), and N(C₁ -C₅ alkanoyl);

R⁷ and R⁸ are each independently selected from C₁ -C₆ alkyl; (C₃ -C₇cycloalkyl) C₁ -C₃ alkylene; (aryl) C₁ -C₃ alkylene; C₃ -C₇ cycloalkyl;and aryl;

R⁹ is C₁ -C₆ alkyl; (C₃ -C₇ cycloalkyl) C₁ -C₃ alkylene; (aryl) C₁ -C₃alkylene; or C₃ -C₇ cycloalkyl;

R¹⁰ and R¹¹ are each independently selected from H; C₁ -C₆ alkyl; (R¹⁴R¹⁵ NOC) C₁ -C₃ alkylene; (R¹⁶ O) C₂ -C₄ alkylene; (C₃ -C₇ cycloalkyl)C₁ -C₃ alkylene; (aryl) C₁ -C₃ alkylene; and C₃ -C₇ cycloalkyl; or,together with the nitrogen atom to which they are attached, form a 4- to7-membered heterocyclic ring which optionally incorporates a furtherheteroatom linkage selected from O, S(O)_(m), NH, N(C₁ -C₄ alkyl), andN(C₁ -C₅ alkanoyl);

R¹² is H; C₁ -C₆ alkyl; (C₃ -C₇ cycloalkyl) C₁ -C₃ alkylene; (aryl) C₁-C₃ alkylene; C₃ -C₇ cycloalkyl; or aryl;

R¹³ is H; C₁ -C₅ alkanoyl; (C₁ -C₄ alkyl)SO₂ ; or H₂ NSO₂ ;

R¹⁴ and R¹⁵ are each independently selected from or C₁ -C₄ alkyl;

R¹⁶ is H; C₁ -C₄ alkyl; or benzyl;

A is a direct link; C₁ -C₆ alkylene optionally branched with C₁ -C₄alkyl; or C₂ -C₆ alkenylene optionally branched with C₁ -C₄ alkyl;

and k and m are each independently selected from 0, 1 and 2;

with the proviso that, for a compound of formula (IE) wherein R² is R⁷COA and A is a direct link, R⁷ is not

(a) methyl, ethyl, phenyl or 4-chlorophenyl when both R³ and R⁴ are H;

(b) methyl when both R³ and R⁴ are methyl; or

(c) phenyl when both R³ and R⁴ are ethyl, or when either of R³ and R⁴ isethyl or butyl and the other is H.

In the above definition, a broken line indicates an optionalcarbon-carbon single bond, aryl means phenyl optionally substituted withone to three substituents independently selected from C₁ -C₄ alkyl, C₁-C₄ alkoxy, halo, F₃ C, NC, H₂ NOC, and HO; heteroaryl means pyrrolyl,furyl, thienyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl or pyrazinyl;and halo means fluoro, chloro, bromo or iodo.

Unless otherwise indicated, alkylene groups having two or more oarbonatoms, alkyl and alkoxy groups having three or more carbon atoms, andalkanoyl, alkenyl and alkynyl groups having four or more carbon atoms,may be straight chain or branched chain.

The compounds of formula (I) may contain one or more asymmetric centresand thus can exist as stereoisomers, i.e. as.enantiomers or asdiastereoisomers. Furthermore, compounds of formula (I) which containalkenyl groups can exist as cis-stereoisomers or trans-stereoisomers. Ineach instance, the invention includes both the separated individualstereoisomers as well as mixtures thereof.

The preferred stereisomers are those compounds of formula (IA) whichpossess the R-configuration at the 2-position of the azetidine,pyrrolidine or piperidine ring, as represented by formula (IA'):##STR3##

Also included in the invention are radiolabelled derivatives ofcompounds of formula (I) which are suitable for biological studies.

The pharmaceutically acceptable salts of the compounds of formula (I)are, for example, non-toxic acid addition salts formed with inorganicacids such as hydrochloric, hydrobromic, sulphuric and phosphoric acid,with organo-carboxylic acids, or with organo-sulphonic acids. For areview of suitable pharmaceutical salts, see J. Pharm. Sci., 1977, 66,1-19.

A preferred group of compounds of formula (I) is that consisting ofcompounds of formula (IA) wherein R² is R⁵ R⁶ C(OH)A or R⁷ COA; R³ is H;C₁ -C₄ alkyl; (benzyl O₂ C) C₁ -C₃ alkylene; (R¹⁰ R¹¹ NOC) C₁ -C₆alkylene; (R¹⁰ R¹¹ NO₂ S)-C₁ -C₃ alkylene; (R⁸ SO₂) C₁ -C₃ alkylene;(R¹² O) C₂ -C₄ alkylene; (R¹³ NH) C₂ -C₄ alkylene; (C₄ -C₆ cycloalkyl)C₁ -C₃ alkylene; or (pyridyl) C₁ -C₃ alkylene; R⁵ and R⁶ are eachindependently selected from H; C₁ -C₄ alkyl; CF₃ ; and cyclopentyl; or,together with the carbon atom to which they are attached, form a 4- to6-membered carbocyclic ring which optionally incorporates an oxygen atomlinkage; R⁷ is C₁ -C₄ alkyl or C₄ -C₆ cycloalkyl; R⁸ is C₁ -C₄ alkyl;R¹⁰ and R¹¹ are each independently selected from H; C₁ -C₄ alkyl; (R¹⁴R¹⁵ NOC ) C₁ -C₃ alkylene; and (R¹⁶ O)-C₂ -C₄ alkylene; or, togetherwith the nitrogen atom to which they are attached, form a 5- to6-membered heterocyclic ring which optionally incorporates an oxygenatom linkage; R¹² is H; C₁ -C₄ alkyl; or benzyl; A is a direct link; C₁-C₄ alkylene; or C₂ -C₄ alkenylene; k is 1; and R¹³, R¹⁴, R¹⁵ and R¹⁶are as previously defined for formula (IA); compounds of formula (IB)wherein R² is R⁵ R⁶ C(OH)A; R³ is H or benzyl; R⁵ and R⁶ together withthe carbon atom to which they are attached form a 4- to 6-memberedcarbocyclic ring; A is ethylene or vinyl; and the broken line is absent;compounds of formula (IC) wherein R² is R⁵ R⁶ C(OH)A or R⁷ COA; R³ is H,C₁ -C₄ alkyl or benzyl; R⁵ and R⁶ are each independently selected from Hand C₁ -C₄ alkyl; or, together with the carbon atom to which they areattached, form a 4- to 6-membered carbocyclic ring; R⁷ is C₁ -C₄ alkyl;A is a direct link; ethylene or vinyl; and the broken line indicates anoptional carbon-carbon single bond; and compounds of formula (IE)wherein R² is R₅ R⁶ C(OH)A; R³ and R⁴ are each independently selectedfrom H, C₁ -C₄ alkyl and benzyl; R⁵ and R⁶ are each C₁ -C₄ alkyl or,together with the carbon atom to which they are attached, form a 4- to6-membered carbocyclic ring; and A is ethylene or vinyl.

A more preferred group of compounds of formula (I) is that consisting ofcompounds of formula (IA) wherein R² is R⁵ R⁶ C(OH)A or R⁷ COA; R³ is H;C₁ -C₃ alkyl; (R¹⁰ R¹¹ NOC) C₁ -C₅ alkylene; CH₃ NHO₂ SCH₂ CH₂ ; CH₃OCH₂ CH₂ ; or (cyclopropyl) CH₂ ; R⁵ is methyl, R⁶ is H methyl, ethyl orCF₃, or R⁵ and R⁶ together with the carbon atom to which they areattached, form a cyclobutyl, cyclopentyl or 3-tetrahydrofuranyl ring; R⁷is methyl; R¹⁰ and R¹¹ are each independently selected from H; methyl;(CH₃)₂ NOCC₂ ; (CH₃)₂ NOCCH₂ CH₂ ; HOCH₂ CH₂ ; and CH₃ OCH₂ CH₂ ; and Ais ethylene, propylene or vinyl; compounds of formula (IC) wherein R² isR⁵ R⁶ C(OH)A; R³ is H or methyl; R⁵ is methyl, R⁶ is H or methyl, or R⁵and R⁶ together with the carbon atom to which they are attached form acyclopentyl ring; A is ethylene or vinyl; and the broken line indicatesan optional carbon-carbon single bond; and a compound of formula (IE)wherein R² is R⁵ R⁶ C(OH)CH₂ CH₂ ; R³ is methyl; R⁴ is H; and R⁵ and R⁶together with the carbon atom to which they are attached form acyclopentyl ring.

A particularly preferred group of compounds of formula (I) is thatconsisting of compounds of formula (IA) wherein R² is R⁵ R⁶ C(OH)A; R³is H; methyl; 2-propyl; CH₂ NHOCCH₂ CH₂ ; (CH₃)₂ NOCCH₂ CH₂ ; CH₃NHOCCH₂ CH₂ CH₂ ; CH₃ NHOCCH₂ CH₂ CH₂ CH₂ CH₂ ; HOCH₂ CH₂ NOCCH₂ CH₂ ;CH₃ OCH₂ CH₂ ; or (cyclopropyl) CH₂ ; R⁵ is methyl, R⁶ is H methyl orCF₃, or R⁵ and R⁶ together with the carbon atom to which they areattached form a cyclobutyl or cyclopentyl ring; and A is ethylene orvinyl; and a compound of formula (IC) wherein R² is CH₃ CH(OH)CH₂ CH₂ ;R³ is methyl; and the broken line is absent.

Especially preferred individual compounds of the invention include:

5-(3-hydroxy-1-butyl)-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole;

3-(N-cyclopropylmethyl-2(R)-pyrrolidinylmethyl)-5-(3-hydroxy-3-methyl-1-butyl)-1H-indole;

5-[2-(1-hydroxycyclopentyl)ethyl]-3-(2(R)-pyrrolidinylmethyl)-1H-indole;

5-[2-(1-hydroxycyolopentyl)ethyl]-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole;

5-[2-(1-hydroxycyclopentyl)ethyl]-3-{N-[2-(N-methylcarbamoyl)ethyl]2(R)-pyrrolidinylmethyl}-1H-indole;

and5-[2-(1-hydroxycyclopentyl)ethyl]-3-{N-[2-(N,N-dimethylcarbamoyl)ethyl]-2(R)-pyrrolidinylmethyl}-1H-indole;

and pharmaceutically acceptable salts thereof, and pharmaceuticallyacceptable solyates (including hydrates) of either entity.

In another aspect, the present invention provides processes for thepreparation of compounds of formula (I), their pharmaceuticallyacceptable salts, and pharmaceutically acceptable solyates (includinghydrates) of either entity, as illustrated below. It will be appreciatedby persons skilled in the art that, within the various processesdescribed, the order of the synthetic steps employed may be varied andwill depend inter alia on factors such as the nature of other functionalgroups present in a particular substrate, the availability of keyintermediates, and the protecting group strategy (if any) to be adopted.Clearly, such factors will also influence the choice of reagent for usein the said synthetic steps. It will also be appreciated that variousstandard functional group interconversions and transformations withincertain compounds of formula (I) will provide other compounds of formula(I); examples are ketones to secondary alcohols and vice versa, andalkenes to alkanes, respectively.

(A1)

A compound of formula (IA) wherein R³ is not H may be obtained byselective N-alkylation of the saturated heterocyclic ring of a compoundof formula (IA) wherein R³ is H, i.e. a compound of formula (IIA):##STR4## wherein R² is as previously defined for formula (I) and k is aspreviously defined for formula (IA), using one or more of the followingmethods.

1. By reaction of a compound of formula (IIA) with a compound of formulaR³ X, wherein R³ is as defined for formula (I) or is a conventionallyprotected precursor thereof (e.g. containing --NH₂ protected asphthalimido), and X is a suitable leaving group, e.g. halo (preferablychloro, bromo or iodo), C₁ -C₄ alkanesulphonyloxy,trifluoromethanesulphonyloxy or arylsulphonyloxy (preferablybenzenesulphonyloxy or p-toluenesulphonyloxy), in the presence of anappropriate base, e.g. sodium or potassium carbonate or bicarbonate, Ortriethylamine, in a suitable solvent such as a C₁ -C₄ alkanol,1,2-dimethoxyethane, acetenitrile, dimethylformamide orN,N-dimethylacetamide, and optionally in the presence of sodium orpotassium iodide. The reaction can be conducted at from about 0° C. toabout 150° C., preferably at from room temperature to 100° C., and,where appropriate, is followed by a standard deprotection step.

2. By reductive alkylation of a compound of formula (IIA) using theappropriate aldehyde-, ketone- or carboxylic acid-containing R³precursor. In the case of an aldehyde or ketone precursor, the substrate(IIA) and carbonyl reagent may be reacted together under conventionalcatalytic hydrogenation conditions or in the presence of sodiumcyanoborohydride, in a suitable solvent such as methanol or ethanol, atabout room temperature. Alternatively, the reductive alkylation may beachieved by a two-step procedure in which the intermediate enamine isformed initially, under conventional conditions, and subsequentlyreduced to the required amine, e.g. using sodium cyanoborohydride intetrahydrofuran-methanol at about room temperature.

In the case of a carboxylic acid precursor, the substrate (IIA) and thesaid acid reagent may be reacted together in the presence of excesssodium borohydride in a suitable solvent; preferably the carboxylic aciditself is used as solvent whenever possible. Since this reductivealkylation proceeds via in situ formation of the corresponding sodiumtriacyloxyborohydride, obvious variations are to employ preformedreagent when commercially available, e.g. sodium triacetoxyborohydride(for N-ethylation), or to preform it in a separate in situ step usingthe stoichiometric amount of carboxylic acid in a suitable solvent. Anexample of the latter procedure involves the treatment of sixequivalents of the carboxylic acid with two equivalents of sodiumborohydride in dry tetrahydrofuran at about room temperature. Whenformation of the required sodium triacyloxyborohydride is complete, thereaction mixture is treated with a solution of one equivalent of thesubstrate (IIA) in the same solvent and the subsequent reaction step isconducted at from about room temperature to about 70° C., preferably50°-55° C.

3. When R³ is C₂ --C₄ alkyl or C₃ -C₇ cycloalkyl, each substituted atthe 2-position with a hydroxy group, by reaction of a compound offormula (IIA) with the appropriate epoxide-containing R³ precursor,optionally in the presence of a tertiary amine base, e.g. triethylamine,and preferably in a suitable solvent such as a C₁ -C₄ alkanol or1,2-dimethoxyethane. The reaction can be conducted at from about 0° C.to about 150° C., preferably at from room temperature to 60° C. usingmethanol as solvent.

When R³ is 2-hydroxyethyl, an "ethylene oxide equivalent" is preferablyemployed. Thus a compound of formula (IIA) may be reacted with ethylenecarbonate in a suitable solvent such as dimethylformamide at about 120°C.

4. When R³ is either C₂ -C₃ alkyl substituted at the 2-position with anelectron withdrawing group such as R⁸ CO, R⁹ O₂ C, R¹⁰ R¹¹ NOC, R¹⁰ R¹¹NO₂ S, R⁸ SO, R⁸ SO₂, or certain aryl or heteroaryl systems (e.g. 2- or4-pyridyl), or also C₄ -C₆ alkyl substituted at the 2-position with R¹⁰R¹¹ NOC, by conjugate addition (Michael-type reaction) of a compound offormula (IIA) to the corresponding α, β-unsaturated ketone-, ester-,amide-, sulphonamide-, sulphoxide-, sulphone-, arene- orheteroarene-containing R³ precursor respectively, wherein R⁸, R⁹, R¹⁰and R¹¹ are as defined for formula (I), optionally in the presence of atertiary amine base such as triethylamine. The reaction may optionallybe conducted in a suitable solvent, e.g. 1,2-dimethoxyethane orN,N-dimethylacetamide, at from about 0° C. to about 100° C., preferablyat about 85° C. or about 100° C. respectively. Alternatively, thereaction may be effected in pyridine, which serves both as tertiaryamine base and as solvent, preferably at about 115° C.

A compound of formula (IIA) may be obtained from a compound of formula(IIIA): ##STR5## wherein R² and k are as previously defined for formula(IIA) and R¹³ forms part of a conventional amino acid N-protectinggroup, i.e. a carbamate, wherein R¹³ is preferably benzyl or t-butyl.N-Deprotection of a compound of formula (IIIA) can be achieved usingstandard methodology; for example, when R¹³ is benzyl, bypalladium-catalysed hydrogenolysis and, when R¹³ is t-butyl, byprotonolysis using trifluoroacetic acid or hydrogen chloride.

Alternatively, when R¹³ is benzyl, N-deprotection can be effected bymodification of the procedure reported in Tetrahedron Letters, 1988, 29,2983, in which (IIIA) is treated with an excess of a tri(loweralkyl)silane in the presence of a palladium(II) salt and an excess of atri(lower alkyl)amine in a suitable solvent such as a C₁ -C₄ alkanol.Preferably the reaction is conducted using triethylsilane, palladium(II)acetate and triethylamine in ethanol at about room temperature.

Depending on the nature of R², a compound of formula (IIIA) can beobtained by a variety of synthetic methods.

For example, when A is C₂ -C₆ alkylene, by reduction of a compound offormula (IVA): ##STR6## wherein R¹⁴ is R⁵ R⁶ C(OH)(CH₂)_(n) or R⁷CO(CH₂)_(n) wherein n is 0, 1, 2, 3 or 4 and R⁵, R⁶ and R⁷ are aspreviously defined for formula (I), and R¹³ and k are as previouslydefined for formula (IIIA). This may be achieved by conventionalcatalytic or catalytic transfer hydrogenation, preferably usingpalladium as catalyst and, in the latter process, ammonium formate asthe hydrogen source. Alternatively, the trialkylsilane/palladium(II)salt procedure described above may be employed.

Clearly, when R¹³ is benzyl, a compound of formula (IVA) may beconverted directly to a compound of formula (IIA) wherein R² is CH₂ CH₂R¹⁴ under these conditions.

Alternatively, when R¹³ is t-butyl, N-deprotection of a compound offormula (IVA) by the protonolysis conditions previously mentioned mayprovide a compound of formula (IIA) wherein R² is CH═CHR¹⁴, i.e. whereinA is C₂ -C₆ alkenylene.

A compound of formula (IVA) may be obtained from a compound of formula(VA): ##STR7## wherein Y is chloro, bromo or iodo (preferably bromo),and R¹³ and k are as previously defined for formula (IVA), with analkene of formula CH₂ ═CHR¹⁴, wherein R¹⁴ is as previously defined forformula (IVA), using the Heck reaction. Thus the desired coupling isachieved using, for example, an excess of the required alkene, in thepresence of palladium(II) acetate, tri-o-tolylphosphine andtriethylamine, in a suitable solvent such as acetonitrile ordimethylformamide, at from about 80° C. to about 160° C.

A compound of formula (VA) may be obtained from a compound of formula(VIA): ##STR8## wherein R¹³, k and Y are as previously defined forformula (VA), by selective and exhaustive reduction of the ketoniccarbonyl group. This may be achieved using an alkali metal borohydridesalt, preferably lithium borohydride, in a suitable solvent such astetrahydrofuran, at from about room temperature to about 70° C.

A compound of formula (VIA) may be obtained as described inWO-A-9206973.

(A2)

An alternative approach to a compound of formula (IA), wherein in R² Ais C₂ -C₆ alkylene, involves the reaction of a compound of formula(VIIA): ##STR9## wherein R³ is as previously defined for formula (I) andk and Y are as previously defined for formula (VIA), with an alkene offormula CH₂ ═CHR¹⁴ wherein R¹⁴ is as previously defined, under the Heckreaction conditions previously described for the conversion of (VA) to(IVA), followed by reduction of the resulting alkene as alreadydescribed for the reduction of (IVA) to (IIIA).

A compound of formula (VIIA) wherein R³ is not H may be obtained byselective N-alkylation of a compound of formula (VIIIA): ##STR10##wherein k and Y are as previously defined for formula (VIIA), by analogywith the procedures described earlier for the conversion of (IIA) to(IA).

When, specifically, R³ is methyl, the said compound of formula (VIIA)may be obtained from a compound of formula (VA) wherein R¹³ is benzyl,and k and Y are as previously. defined for formula (VA), by reductionwith lithium aluminium hydride, as described in WO-A-9206973 for thecase wherein Y is bromo.

A compound of formula (VIIIA) may be obtained from a compound of formula(VA) wherein R¹³, k and Y are as previously defined for formula (VA) bythe standard N-deprotection methodology already described. Preferablyhowever, when R¹³ is benzyl, deprotection is effected by anon-hydrogenolytic procedure such as protonolysis in a suitable solventusing, for example, hydrogen bromide in glacial acetic acid or hydrogenchloride in methanol, at about room temperature, a Lewis acid-catalysednucleophilic deprotection using, for example, boron trifluoride etherateand excess ethanethiol in a suitable solvent such as dichloromethane atabout room temperature, or an alkaline deprotection using, for example,potassium hydroxide in a suitable solvent such as a C₁ -C₄ alkanol,preferably n-butanol.

(A3)

Certain compounds of formula (IA) wherein R² is R⁷ COA, wherein R⁷ is aspreviously defined for formula (I) but is not aryl and A is a directlink, may be obtained by analogy with the processes described previouslyunder (A1) and (A2) wherein the compound of formula (VA) or (VIIA) iscoupled under Heck reaction conditions with an enol ether of formula(IXA): ##STR11## wherein R¹⁵ and R¹⁶ are both H, or one of R¹⁵ and R¹⁶is H and the other is C₁ -C₅ alkyl, (C₃ -C₇ cycloalkyl) C₁ -C₂ alkyleneor (aryl) C₁ -C₂ alkylene, or R¹⁵ and R¹⁶ together with the carbon atomto which they are attached form C₃ -C₇ cycloalkyl, and R¹⁷ is C₁ -C₄alkyl, followed by acid-catalysed hydrolysis of the intermediate,coupled enol ether. Because of the commercial availability of vinylethers, i.e. compounds of formula (IXA) wherein R¹⁵ and R¹⁶ are both H,this is a particularly convenient method for introducing an acetyl groupinto the 5-position of a compound of formula (VA) or (VIIA).

(A4)

A compound of formula (IA) wherein R² is R⁵ R⁶ C(OH)A, wherein R⁵ and R⁶are as previously defined for formula (I) and A is a direct link, mayalso be obtained by analogy with the processes described under (A1) and(A2) wherein the 5-substituent is introduced into a compound of formula(VA) or (VIIA) by coupling a 5-organometallic substituted derivativethereof, e.g. an aryllithium or Grignard reagent, with the appropriatealdehyde or ketone of formula R⁵ R⁶ C═O wherein R⁵ and R⁶ are as definedabove.

For example, (VA) or (VIIA) is treated with the required excess of asolution of t-butyllithium in hexane in a suitable anhydrous solvent,such as dry tetrahydrofuran, at from about -50° C. to about -70° C.; ifrequired, the temperature may be allowed to rise to about roomtemperature to ensure complete formation of the desired 5-lithiumderivative. Generally, the reaction mixture is again cooled to about-70° C. before addition of the appropriate aldehyde or ketone andsubsequent quenching.

Variations include the sequential use of potassium hydride andt-butyllithium or prior protection of the indole 1-position, e.g. with atriisopropylsilyl group, followed by treatment with n-butyllithium, togenerate the desired 5-lithium derivative.

(A5)

A compound of formula (IA) wherein R² is R⁷ COA, wherein R⁷ is aspreviously defined for formula (I) and A is a direct link, may. also beobtained from a compound of formula (VA) or (VIIA) via theorganometallic derivatives identified in (A4) above by reaction with theappropriate electrophilic acylation reagent, e.g. ester or nitrile(followed in the latter case by hydrolysis of the intermediate iminesalt).

(A6).

As previously suggested, certain compounds of formula (IA) can beprepared from other compounds of formula (IA) by, for example, thefollowing conventional functional group interconversions andtransformations:

(a) a compound of formula (IA) wherein R² contains a secondary alcoholgroup is obtainable from the corresponding ketone of formula (IA) byreduction. The choice of appropriate reducing agent will be dependent,inter alia, on the nature of R³ but will include aluminium hydride andborohydride salts. Preferably the reaction is conducted using sodiumborohydride in a suitable solvent such as a C₁ -C₄ alkanol, preferablyethanol, at about room temperature.

The reverse interconversion also forms part of the invention and therelevant criteria for selection of an appropriate oxidising reagent willbe evident to persons skilled in the art. A preferred procedure is theuse of activated manganese dioxide in a suitable solvent such as anacetonitrile-dichloromethane mixture at about room temperature;

(b) a compound of formula (IA) wherein R² contains a tertiary alcoholgroup is obtainable from the corresponding ketone of formula (IA) byreaction with the required excess of a conventional organometallicreagent such as an alkyl- or cycloalkyl-lithium or Grignard reagent;

(c) a compound of formula (IA) wherein in R² A is C₂ -C₆ alkylene isobtainable from the corresponding compound of formula (IA) wherein A isC₂ -C₆ alkenylene by a variety of alkene reduction procedures alreadydescribed;

(d) a compound of formula (IA) wherein R³ contains a R¹⁰ R¹¹ NOCsubstituent is obtainable from a corresponding ester of formula (IA),i.e. wherein R³ contains a R⁹ O₂ C substituent, by direct aminationusing an amine of formula R¹⁰ R¹¹ NH. The reaction is preferably carriedout using an excess of the amine in a suitable solvent such as a C₁ -C₄alkanol at an elevated temperature, e.g. the reflux temperature of thereaction medium. For low boiling amines, the reaction is preferablyconducted in a sealed vessel.

The same over-all transformation can be effected indirectly via theintermediacy of the corresponding carboxylic acid, i.e. a compound offormula (IA) wherein R³ contains a HO₂ C substituent. Depending on thenature of the ester, its deprotection may be achieved by acid oralkaline hydrolysis, protonolysis (e.g. when R⁹ is t-butyl) orhydrogenolysis (e.g. when R⁹ is benzyl). Conversion of the acid to therequired amide may also be achieved by a variety of methods. Forexample, the acid may be activated by formation of the correspondingacyl halide, e.g. bromide or chloride, followed by reaction of thelatter with an amine of formula R¹⁰ R¹¹ NH optionally in the presence ofa reaction-inert base to act as acid scavenger. Preferably, any of ahost of standard amide bond-forming (peptide coupling) reagents may beused. For example, the acid may be activated using a carbodiimide suchas 1-ethyl-3-dimethylaminopropylcarbodiimide, optionally in the presenceof 1-hydroxybenzotriazole and a reaction-inert amine such asN-methylmorpholine, followed by in situ reaction of the activated acidwith an amine of formula R¹⁰ R¹¹ NH;

(e) a compound of formula (IA) wherein R³ contains a R⁸ SO or a R⁸ SO₂substituent is obtainable from the corresponding sulphide of formula(IA), i.e. wherein R³ contains a R⁸ S substituent, either by controlledoxidation using a stoichiometric amount of oxidising agent, or by usingthe required excess of oxidising agent, respectively. Suitable oxidisingagents are, for example, a peracid such as metachloroperbenzoic acid,hydrogen peroxide or nitronium tetrafluoroborate.

(B)

A compound of formula (IB) may, in general terms, be obtained by analogywith the processes (A1)-(A6) already described above for the preparationof compounds of formula (IA).

For example, comparably with process (A1), a compound of formula (IB)wherein R³ is not H may be obtained from a compound of formula (IB)wherein R³ is H, i.e. a compound of formula (IIB): ##STR12## wherein R²is as previously defined for formula (I) and the broken line is aspreviously defined for formula (IB), by analogy with the methods alreadydescribed for the conversion of a compound of formula (IIA) to acompound of formula (IA).

Certain compounds of formula (IIB) wherein both R² and the heterocyclic3-substituent contain fully saturated carbon-carbon. bonds may beconveniently obtained from a compound of formula (IIIB): ##STR13##wherein R¹⁸ is a protecting group which is removable under theconventional catalytic hydrogenation conditions previously described forthe conversion of (IVA) to (IIIA), and R¹⁴ is as previously defined forformula (IVA). Preferably R¹⁸ is benzyl.

A compound of formula (IIIB) may be obtained from a compound of formula(IVB): ##STR14## wherein Y is as previously defined for formula (VA) andR¹⁸ is as previously defined for formula (IIIB), by analogy with theHeck reaction procedure already described for the conversion of (VA) to(IVA).

A compound of formula (IVB) may be obtained by reduction of a compoundof formula (VB): ##STR15## wherein Y and R¹⁸ are as previously definedfor formula (IVB). This may be achieved, for example, using lithiumaluminium hydride in a suitable solvent such as tetrahydrofuran at fromabout room temperature to about 70° C., preferably at 65° to 70° C.

A compound of formula (VB) may be obtained by coupling a compound offormula (VIB): ##STR16## wherein Y is as previously defined for formula(VB), with a compound of formula (VIIB): ##STR17## wherein R¹⁸ is asdefined for formula (VB), in a suitable solvent such as glacial aceticacid preferably at about 115°-120° C.

Clearly, by analogy with process (A2), when R¹⁸ is a value of R³ aspreviously defined for formula (IB), certain compounds of formula (IB)may be obtained directly from a compound of formula (IVB) using the Heckreaction step previously described, optionally followed by furthertransformations of the R² substituent (vide supra). Such compounds offormula (IVB) may also be used in processes analogous to (A3), (A4) and(A5).

Most directly, however, certain compounds of formula (IB) may beobtained from a compound of formula (I) wherein R¹ is H and R² is aspreviously defined for formula (I), obtainable from a compound offormula (VIB) by previously described methodology, by coupling with acompound of formula (VIIB) wherein R¹⁸ is a value of R³ as previouslydefined for formula (IB).

(C)

A compound of formula (IC) may also, in general terms, be obtained byanalogy with process (A1)-(A6).

For example, comparably with process (A1), a compound of formula (IC)wherein R³ is not H may be obtained from a compound of formula (IC)wherein R³ is H, i.e. a compound of formula (IIC): ##STR18## wherein R²is as previously defined for formula (I) and the broken line is aspreviously defined for formula (IC), by analogy with the methods alreadydescribed for the conversion of (IIA) to (IA).

A compound of formula (IIC) may be obtained from a compound of formula(IIIC): ##STR19## wherein R¹³ is as previously defined for formula(IIIA) and R² is as previously defined for formula (IIC), by analogywith the methods already described for the conversion of (IIIA) to(IIA).

Certain compounds of formula (IIIC) may be obtained from a compound offormula (IVC): ##STR20## wherein R¹⁴ is as previously defined forformula (IVA) and R¹³ is as previously defined for formula (IIIC), byanalogy with the methods already described for the conversion of (IVA)to (IIIA).

A compound of formula (IVC) may be obtained from a compound of formula(VC): ##STR21## wherein Y is as previously defined for formula (VA) andR¹³ is as previously defined for formula (IVC), by analogy with theHeck. reaction procedure already described for the conversion of (VA) to(IVA).

A compound of formula (VC) may be obtained by reaction of a compound offormula (VIB) with a compound of formula (VIC): ##STR22## wherein R¹³ isas previously defined for formula (VC), in the presence of a base, e.g.potassium hydroxide, in a suitable solvent such as a C₁ -C₃ alkanol,preferably methanol, at about the reflux temperature of the reactionmedium. Alternative reaction conditions are described in EP-A-0303507.

Again, several variations of the above process are possible. Forexample, when certain compounds of formula (VIIC): ##STR23## wherein R³is as previously defined for formula (IC), are readily accessible, thesaid compounds may be condensed directly with either a compound offormula (VIB) or a compound of formula (VIIIC): ##STR24## wherein R¹⁴ isas previously defined for formula (IVC). A compound of formula (VIIIC)may be obtained from a compound of formula (VIB) using the Heckprocedure previously described for the conversion of (VA) to (IVA).

Clearly, and most directly, said compounds of formula (VIIC) may becondensed with a compound of formula (I), wherein R¹ is H and R² is aspreviously defined for formula (I), which in turn is obtainable from acompound of formula (VIB) by previously described methodology.

By analogy with process (A2), the condensation product of (VIIC) and(VIB) is then subjected to the above Heck procedure. Alternatively, itmay be used in processes analogous to (A3), (A4) and (A5).

More specifically, when R³ is benzyl, i.e. when N-benzyl-4-piperidone isused as starting material, this will provide an alternative route to acompound of formula (IIC) wherein the broken line represents no bond.

(D)

A compound of formula (ID) is obtainable by analogy with the processesdescribed in (C) for the preparation of compounds of formula (IC).

For example, a compound of formula (ID) wherein R³ is not H may beobtained from a compound of formula (ID) wherein R³ is H, i.e. acompound of formula (IID): ##STR25## wherein R² is as previously definedfor formula (I) and the broken line is as previously defined for formula(ID), by analogy with the methods already described for the conversionof (IIA) to (IA).

A compound of formula (IID) may be obtained by analogy with the processsteps described above for the preparation of a compound of formula(IIC), using the 3-piperidone analogues of (VIC) and (VIIC).

(E)

Using an approach similar to that of process (A1), a compound of formula(IE) may be obtained from a compound of formula (IIE): ##STR26## whereinR² is as previously defined for formula (I), by analogy with the methodsalready described for the conversion of (IIA) to (IA). However, when R³and R⁴ are different but are not H, or when only one of R³ and R⁴ is H,it may be advantageous to employ an amine-protecting group strategy inorder to obviate dialkylation of the primary amino group; examples ofconventional amine-protecting groups are benzyl, trifluoroacetyl,t-butoxycarbonyl, benzyloxycarbonyl and 2,2,2-trichloroethoxycarbonyl.The person skilled in the art will recognise the most suitableprotecting group required when consideration.is given, inter alia, tothe alkylating reagents to be used and the functional groups present inthe starting material and product; such a person will also recognisewhen conventional protection of the indole 1-position is beneficial.When R³ and R⁴ are identical but are not H, the required compound offormula (IE) may be conveniently obtainable in a one-pot reactionwithout the need for primary amine protection.

Certain compounds of formula (IIE), namely those which do not contain aketone group (unless appropriately protected) within the R² substituent,may be obtained from a compound of formula (IIIE): ##STR27## wherein R²is as previously defined for formula (IIE), by deprotection of the aminogroup. This is achievable, for example, by treating the phthalimidederivative with an excess of hydrazine hydrate in a C₁ -C₄ alkanol,preferably ethanol, as solvent at from about room temperature to aboutthe reflux temperature of the reaction medium, preferably at 75°-80° C.

Certain compounds of formula (IIIE) may be obtained from a compound offormula (IVE): ##STR28## wherein R¹⁴ is as previously defined forformula (IVA), by analogy with the methods already described for theconversion of (IVA) to (IIIA).

A compound of formula (IRE) may be obtained from a compound of formula(VE): ##STR29## wherein Y is as previously defined for formula (VA), byanalogy with the Heck reaction procedure already described for theconversion of (VA) to (IVA).

A compound of formula (VE) may be obtained using standard Fischer indolesynthesis methodology in which, for example, the appropriate4-halophenylhydrazine hydrochloride salt is reacted with4-phthalimido-n-butyraldehyde diethyl acetal, as described in U.S. Pat.No. 4,252,803 for the corresponding 5-bromo analogue.

In an alternative process, analogous to process (A2), a compound offormula (IE) may be obtained directly from a compound of formula (VIE):##STR30## wherein R³ and R⁴ are as previously defined for formula (IE)and Y is as previously defined for formula (VE), by analogy with theNeck reaction procedure mentioned above for the conversion of (VA) to(IVA).

The indoles of formula (VIE) may also be obtained using the Fischerindole reaction, examples of which are illustrated in U.S. Pat. No.4,252,803.

A further convenient process for the preparation of certain compounds offormula (IE) via a compound of formula (VIE) involves the reaction of acompound of formula (VIB) with oxalyl chloride in a suitable solventsuch as anhydrous tetrahydrofuran at from about 0° C. to about 30° C.,preferably at about room temperature, followed by in situ treatment ofthe intermediate acyl chloride with an amine of formula R³ R⁴ NH,wherein R³ and R⁴ are as previously defined for formula (IE), at fromabout 0° C. to about room temperature, preferably at about 0° C. Next,the resulting amide is exhaustively reduced to a compound of formula(VIE) using a powerful reducing agent such as lithium aluminium hydridein a suitable solvent such as anhydrous tetrahydrofuran at from aboutroom temperature to about 70° C., preferably at 65° to 70° C.

Clearly, if R³ is benzyl and is removed during the further processing of(VIE) to a compound of formula (IE), then further elaboration of theterminal secondary amine group, as previously described, will providefurther compounds of formula (IE).

Further variants include the use of a compound of formula (VIE) inprocess analogous to (A3), (A4) and (A5), and also processes analogousto those described in (A6).

Compounds of formula CH₂ ═CHR¹⁴ wherein R¹⁴ is as previously defined forformula (IVA), those of formulae (IXA), (VIB) and (VIIB), and also thoseof formulae (VIC) and (VIIC) together with the corresponding3-piperidones, and the various reagents required for the processeshereinbefore disclosed, when neither commercially available norsubsequently described, can be obtained either by analogy with thereactions described in the Examples and Preparations sections or byconventional synthetic procedures, in accordance with standard textbookson organic chemistry or literature precedent, from readily accessiblestarting materials using appropriate reagents and reaction conditions.Clearly, when the preferred stereoisomers of formula (IA') are required,the compounds of formulae (VIA) will possess the 2R-configuration.

Persons skilled in the art will recognise that the alkenes depictedhereinbefore may be obtained in cis- or trans-stereoisomeric forms, oras mixtures of cis- and trans-stereoisomers, and are represented in onesuch form only in the interests of clarity and convenience. Such personswill also be aware of variations of, and alternatives to, thosereactions described hereinafter for the preparation of compounds offormula (I).

The pharmaceutically acceptable acid addition salts of compounds offormula (I) may also be prepared in a conventional manner. For example asolution of the free base is treated with the appropriate acid, eitherneat or in an appropriate solvent, and the resulting salt isolatedeither by filtration or by evaporation under vacuum of the reactionsolvent. Certain such salts may be formed or interconverted usingion-exchange resin techniques.

The compounds of the invention are selective agonists at the "5-HT₁-like" subtype of the 5-HT (serotonin) receptor and are therefore usefulin the curative or prophylactic treatment of migraine and associatedconditions such as cluster headache, chronic paroxysmal hemicrania andheadache associated with vascular disorders. Certain of these compoundsare also agonists at central 5-HT₁ receptors and are therefore usefulfor the treatment of depression, anxiety, eating disorders, obesity,drug abuse and emesis.

The in vitro evaluation of the "5-HT₁ -like" receptor agonist activityof the compounds of the invention is carried out by testing the extentto which they mimic sumatriptan in contracting the isolated dogsaphenous vein strip (P.P.A. Humphrey et al., Brit. J. Pharmacol., 1988,94, 1123). This effect can be blocked by methiothepin, a known 5-HTantagonist. Sumatriptan is known to be useful in the treatment ofmigraine and produces a selective increase in carotid vascularresistance in the anaesthetized dog and a consequent decrease in carotidarterial blood flow. It has been suggested (W. Feniuk et al., Brit. J.Pharmacol., 1989, 96, 83) that this is the basis of its efficacy.

The 5-HT₁ agonist activity of the compounds of the invention can bemeasured in in vitro receptor binding assays as described for the5-HT_(1A) receptor, using rat cortex as the receptor source and [³H]8-OH-DPAT as the radioligand (D. Hoyer et al., Europ. J. Pharmacol.,1985, 118, 13), and as described for the 5-HT_(1D) receptor, usingbovine caudate as the receptor source and [³ H]5-HT as the radioligand(R. E. Heuring and S. J. Peroutka, J. Neuroscience, 1987, 7, 894).

In therapy, the compounds of formula (I), their pharmaceuticallyacceptable salts, and pharmaceutically acceptable solyates of eitherentity, can be administered alone, but will generally be administered inadmixture with a pharmaceutical carrier selected with regard to theintended route of administration and standard pharmaceutical practice.For example, they can be administered orally in the form of tabletscontaining such excipients as starch or lactose, or in capsules orovules either alone or in admixture with excipients, or in the form ofelixirs, solutions or suspensions containing flavouring or colouringagents. They can also be injected parenterally, for example,intravenously, intramuscularly or subcutaneously. For parenteraladministration, they are best used in the form of a sterile aqueoussolution which may contain other substances, for example, enough saltsor glucose to make the solution isotonic with blood. For buccal orsublingual administration they may be administered in the form oftablets or lozenges which can be formulated in a conventional manner.

For oral, parenteral, buccal and sublingual administration to patients,the daily dosage level of the compounds of formula (I), theirpharmaceutically acceptable salts, and pharmaceutically acceptablesolvates of either entity, will be from 0.1 ng to 20 mg/Kg (in single ordivided doses). Thus tablets or capsules will contain from 5 ng to 0.5 gof active compound for administration singly, or two or more at a time,as appropriate. The physician in any event will determine the actualdosage which will be most suitable for an individual patient and it willvary with the age, weight and response of the particular patient. Theabove dosages are exemplary of the average case; there can, of course,be individual instances where higher or lower dosage ranges are metired,and such within the scope of this invention.

Alternatively, the compounds of formula (I), their pharmaceuticallyacceptable salts, and pharmaceutically acceptable solvates of eitherentity, can be administered in the form of a suppository or pessary, orthey may be applied topically in the form of a lotion, solution, cream,ointment or dusting powder. For example, they can be incorporated into acream consisting of an aqueous emulsion or polyethylene glycols orliquid paraffin; or they can be incorporated, at a concentration of from1 to 10%, into an ointment consisting of a white wax or white softparaffin base together with such stabilisers and preservatives as may berequired.

The compounds of formula (I), their pharmaceutically acceptable salts,and pharmaceutically acceptable solyates of either entity, can also beadministered intranasally or by inhalation and are convenientlydelivered in the form of a solution or suspension from a pump spraycontainer, which is squeezed or pumped by the patient, or as an aerosolspray presentation from a pressurised container or a nebuliser with theuse of a suitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurised aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount. Thepressurised container or nebuliser may contain a solution or suspensionof the active compound. Capsules and cartridges (made, for example, fromgelatin) for use in an inhaler or insufflator may be formulatedcontaining a powder mix of a compound of the invention and a suitablepowder base such as lactose or starch.

Aerosol formulations are preferably arranged so that each metered doseor "puff" of aerosol contains from 1 ng to 1000 μg of a compound offormula (I), or a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable solvate of either entity, for delivery tothe patient. The overall daily dose with an aerosol will be within therange of from 5 ng to 10 mg which may be administered in a single doseor, more usually, in divided doses throughout the day.

Thus the invention provides pharmaceutical compositions comprising acompound of formula (I), or a pharmaceutically acceptable salt thereof,or a pharmaceutically acceptable solrate (including hydrate) of eitherentity, together with a pharmaceutically acceptable diluent or carrier.

The invention also provides a compound of formula (I), or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate (including hydrate) of either entity, or apharmaceutical composition containing any of the foregoing, for use as amedicament.

The invention further includes the use of a compound of formula (I), ora pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate (including hydrate) of either entity, or apharmaceutical composition containing any of the foregoing, both for themanufacture of a medicament for the curative or prophylactic treatmentof migraine or an associated condition such as cluster headache, chronicparoxysmal hemicrania or headache associated with a vascular disorder,or of depression, anxiety, an eating disorder, obesity, drug abuse oremesis, and also for the manufacture of a medicament for the curative orprophylactic treatment of a medical condition for which a selectiveagonist of 5-HT₁ -like receptors is indicated.

In a further aspect, the invention provides both a method of treating ahuman being to cure or prevent migraine or an associated condition suchas cluster headache, chronic paroxysmal hemicrania or headacheassociated with a vascular disorder, or depression, anxiety, an eatingdisorder, obesity, drug abuse or emesis, and also a method of treating ahuman being to cure or prevent a medical condition for which a selectiveagonist of 5-HT₁ -like receptors is indicated, which comprises treatingsaid human being with an effective amount of a compound of formula (I),or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate (including hydrate) of either entity, or apharmaceutical composition containing any of the foregoing.

The syntheses of the compounds of the invention and of the intermediatesfor use therein are illustrated by the following Examples andPreparations. The purity of the compounds was routinely monitored bythin layer chromatography (Rf) using Merck Kieselgel 60 F₂₅₄ plates andthe following solvent systems (SS):

1. dichloromethane:methanol:0.880 aqueous ammonia, 93:7:1;

2. dichloromethane:ethanol:0.880 aqueous ammonia, 90:10:1;

3. hexane:ether, 1:1;

4. dichloromethane:ethanol:0.880 aqueous ammonia, 25:8:1;

5. hexane:ethyl acetate, 3:1;

6. ethyl acetate:diethylamine, 95:5;

7. dichloromethane:methanol:0.880 aqueous ammonia, 90:10:1;

8. dichloromethane:methanol, 99:1;

9. dichloromethane:methanol:0.880 aqueous ammonia, 90:10:2;

10. hexane:ethyl acetate, 1:1;

11. dichloromethane:methanol:0.880 aqueous ammonia, 89:10:1;

12. dichlormethane:methanol:0.880 aqueous ammonia, 80:20:2;

13. dichloromethane:methanol:0.880 aqueous ammonia, 90:10:0.5;

14. hexane:ethyl acetate:diethylamine, 70:25:5;

15. dichloromethane:methanol:0.880aqueous ammonia, 86.5:12.5:1;

16. dichloromethane;

17. ethyl acetate;

18. dichloromethane:methanol, 98:2;

19. dichloromethane:ethanol, 95:5;

20. dichloromethane:methanol, 95:5.

¹ H Nuclear magnetic reasonance (NMR) spectra were recorded using eithera Nicolet QE-300 or a Bruker AC-300 spectrometer and were in all casesconsistent with the proposed structures. Chemical shifts (δ) are givenin parts-per-million downfield from tetramethylsilane using conventionalabbreviations for designation of major peaks: s, singlet; d, doublet;dd, doublet of doublets; t, triplet; m, multiplet; br, broad.

LRMS means low resolution mass spectrum.

HRMS means high resolution mass spectrum.

Room temperature means 20°-25° C.

EXAMPLE 15-(3-Hydroxy-3-methyl-1-but-1-enyl)-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole

A stirred solution of5-bromo-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole (WO-A-92/06973;879 mg, 3.0 mmol), 2-methylbut-3-en-2-ol (0.408 ml, 3.9 mmol),tri-o-tolylphosphine (273 mg, 0.90 mmol), palladium(II) acetate (45 mg,0.20 mmol), triethylamine (0.84 ml, 6.0 mmol) and acetonitrile (50 ml),under nitrogen, was heated under reflux for 24 hours, allowed to cool,then partitioned between ethyl acetate and 2M aqueous sodium carbonatesolution. The organic phase was separated, washed sequentially with 2Maqueous sodium carbonate solution (×2) and brine (×1), dried (Na₂ SO₄)and evaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel, eluting with a solvent gradient of0.880 aqueous ammonia:methanol: dichloromethane (0:5:95 to 0.5:5:95), toafford the title compound as a solid (226 mg), m.p. 155°-158° C. Rf 0.10(SS 1). [α]_(D) ²⁵ +81° (c=0.1, CH₃ OH). Found: C,75.27; H,8.96; N,8.99.C₁₉ H₂₆ N₂ O; 0.25 H₂ O requires C,75.33; H,8.82; N,9.25%.

EXAMPLE 25-(3-Hydroxy-3-methyl-1-butyl)-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole

A solution of the title compound of Example 1 (500 mg, 1.65 mmol) inethanol (50 ml) was hydrogenated over 5% palladium on charcoal (250 mg)at 15 p.s.i. (1.04 bar) and room temperature for 18 hours, thenfiltered. Evaporation of the filtrate under reduced pressure yielded anoil, which was azeotroped with dichloromethane (2×50 ml) to give a whitefoam (488 mg). Purification of the foam by column chromatography onsilica gel, eluting with a solvent gradient of 0.880 aqueousammonia:methanol:dichloromethane (0:0:100 to 0:5:95 to 0.5:3.5:96),provided the title compound as a white solid (318 mg), m.p. 125°-126° C.[α]_(D) ²⁵ +93° (c=0.1, CH₃ OH). Found: C,74.61; H,9.33; N,8.92. C₁₉ H₂₈N₂ O; 0.05 CH₂ Cl₂ ; 0.17 H₂ O requires C,74.36; H,9.31; N,9.11%.

EXAMPLE 35-(3-Hydroxy-1-but-1-enyl)-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole

Obtained by a procedure similar to that described in Example 1, usingbut-3-en-2-ol as the appropriate alkene, as a foam. Rf 0.10 (SS 2).Found: C,72.53; H,8.23; N,9.28. C₁₈ H₂₄ N₂ O; 0.20 CH₂ Cl₂ requiresC,72.53; H,8.16; N,9.30%.

EXAMPLE 45-(3-Hydroxy-1-butl)-3-(N-methyl-2-(R)-pyrrolidinylmethyl)-1H-indole

Obtained from the title compound of Example 3 by a procedure similar tothat described in Example 2, but using 10% palladium on charcoal ascatalyst, as a foam. Rf 0.80 (SS 4). [α]_(D) ²⁵ +76° (c=0.1, CH₃ OH).Found: C,73.95; H,9.03; N,9.70. C₁₈ H₂₆ N₂ O; 0.25 H₂ O requiresC,74.31; H,9.18; N,9.63%.

EXAMPLE 55-[2-(1-Hydroxycyclopentyl)ethenyl]-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole(a) 1-Vinylcyclopentanol

A solution of cyclopentanone (7.5 g, 0.09 mol) in dry tetrahydrofuran(30 ml) was added dropwise to a stirred 1M solution of vinylmagnesiumbromide in tetrahydrofuran (99 ml, 0.099 mol) under nitrogen at about 0°C. The reaction mixture was stirred at room temperature for 18 hours,cooled to about 0° C., treated drop-wise with saturated aqueous ammoniumchloride solution (45 ml) and exhaustively extracted with ethyl acetate.The combined extracts were dried (Na₂ SO₄) and evaporated under reducedpressure, then the residual liquid distilled to give1-vinylcyclopentanol as a colourless oil (5.68 g), b.p. 92°-100° C./100mm. Rf 0.40 (SS 3).

(b)

The title compound was obtained by a procedure similar to that describedin Example 1, using 1-vinylcyclopentanol as the appropriate alkene, asan oil. Rf 0.30 (SS 2). [α]_(D) ²⁵ +89° (c=0.1, CH₃ OH). Found: C,76.15;H,8.50; N,8.62. C₂₁ H₂₈ N₂ O; 0.33 H2O requires C,76.31; H,8.74;N,8.48%.

EXAMPLE 65-[2-(1-Hydroxycyclopentyl)ethyl]-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole

Obtained from the title compound of Example 5 by a procedure similar tothat described in Example 2 as a foam. Rf 0.30 (SS 2). [α]_(D) ²⁵ +70°(c=0.1, CH₃ OH). Found: C,75.12; H,9.12; N,8.51. C₂₁ H₃₀ N₂ O; 0.50 H₂ Orequires C,75.17; H,9.31; N,8.35%.

EXAMPLE 75-[2-(1-Hydroxycyclohexyl)ethenyl]-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole(a) 1-Vinylcyclohexanol

Obtained by a procedure similar to that described in Example 5(a), usingcyclohexanone as the appropriate ketone, as an oil. Instead ofdistillation, the crude product was purified by column chromatography onsilica gel, eluting with ether:hexane (2.5:100). Rf 0.50 (SS 3). Found:C,75.83; H,11.91. C₈ H₁₄ O; 0.04 (C₂ H₅)₂ O requires C,75.53; H,11.89%.

(b)

The title compound was obtained by a procedure similar to that describedin Example 1, using 1-vinylcyclohexanol as the appropriate alkene, as anoil.

Rf 0.17 (SS 2). [α]_(D) ²⁵ +52° (c=0.1, CH₃ OH). Found: C,75.91; H,8.85;N,8.06. C₂₂ H₃₀ N₂ O; 0.50 H₂ O requires C,76.03; H,9.04; N,7.94%.

EXAMPLE 85-[2-(1-Hydroxycyclohexyl)ethyl]-3-(N-methyl-2(R)-pyrrolidinylmethyl-1H-indole

Obtained from the title compound of Example 7 by a procedure similar tothat described in Example 2 as a foam. Rf 0.25 (SS 2). [α]_(D) ²⁵ +56°(c=0.1, CH₃ OH). Found: C,74.24; H,8.86; N,8.04. C₂₂ H32N₂ O; 0.20 CH₂Cl₂ requires C,74.57; H,9.13; N,7.84%.

EXAMPLE 95-(3-Ethyl-3-hydroxy-1-pent-1-enyl)-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole

(a) 3-Ethylpent-1-en-3-ol

Obtained by a procedure similar to that described in Example 5(a), usingpentan-3-one as the appropriate ketone, as an oil. Purification waseffected by column chromatography on silica gel, eluting withether:hexane (1:1). Rf 0.40 (SS 3).

(b)

The title compound was obtained by a procedure similar to that describedin Example 1, using 3-ethylpent-1-en-3-ol as the appropriate alkene, asan oil. Rf 0.25 (SS 2). [α]_(D) ²⁵ +72° (c=0.1, CH₃ OH). Found: C,74.72;H,8.56; N,8.68. C₂₁ H₃₀ N₂ O: 0.67 H₂ O requires C,74.51; H,8.93;N,8.28%.

EXAMPLE 105-(3-Ethyl-3-hydroxy-1-pentyl)-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole

Obtained from the title compound of Example 9 by a procedure similar tothat described in Example 2 as a foam. Rf 0.25 (SS 2). [γ]_(D) ²⁵ +64°(c=0.1, CH₃ OH). Found: C,72.31; H,9.15; N,8.31. C₂₁ H₃₂ N₂ O; 0.25 CH₂Cl₂ ; 0.20 H₂ O requires C,72.22; H,9.38; N,7.93%.

EXAMPLE 115-2-(4-Hydroxy-4-tetrahydropyranyl)ethenyl]-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole

(a) 4-Vinyl tetrahydro-4H-pyran-4-ol

Obtained by a procedure similar to that described in Example 5(a), usingtetrahydro-4H-pyran-4-one as the appropriate ketone, as an oil.Purification was effected by column chromatography on silica gel,eluting with ethyl acetate:hexane (1:3). Rf 0.35 (SS 5). Found: C,63.56;H,9.29. C₇ H₁₂ O₂ ; 0.25 H₂ O requires C,63.37; H,9.50%.

(b)

The title compound was obtained by a procedure similar to that describedin Example 1, using 4-vinyl tetrahydro-4H-pyran-4-ol as the appropriatealkene, as a foam. Rf 0.28 (SS 6). [α]_(D) ²⁵ +80° (c=0.1, CH₃ OH).Found: C,70,33; H,8.02; N,8.09. C₂₁ H₂₈ N₂ O₂ ; 0.25 CH₂ Cl₂ requiresC,70.57; H,7.94; N,7.74%.

EXAMPLE 125-[2-(4-Hydroxy-4-tetrahydropyranyl)ethyl]-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole

Obtained from the title compound of Example 11 by a procedure similar tothat described in Example 2, but using 10% palladium on charcoal ascatalyst, as a foam. Rf 0.27 (SS 6). [α]_(D) ²⁵ +51° (c=0.1, CH₃ OH).Found: C,70.58; H,8.71; N,7.71. C₂₁ H₃₀ N₂ O₂ ; 0.20 CH₂ Cl₂ requiresC,70.83; H,8.52; N,7.79%.

EXAMPLE 135-[2-(1-Hydroxycyclobutyl)ethenyl]-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole

(a) 1-Vinylcyclobutanol

Obtained by a procedure similar to that described in Example 5(a), usingcyclobutanone as the appropriate ketone, as an oil. Rf 0.40 (SS 3).

(b)

The title compound was obtained .by a procedure similar to thatdescribed in Example 1, using 1-vinylcyclobutanol as the appropriatealkene, as an oil. Rf 0.30 (SS 2). [α]_(D) ²⁵ +73° (c=0.1, CH₃ OH).Found: C,77.60; H,8.66; N,8.83. CH₂₀ H₂₆ N₂ O requires C,77.38; H,8.44;N,9.03%

EXAMPLE 145-[2-(1-Hydroxycyclobutyl)ethyl]-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole

Obtained from the title compound of Example 13 by a procedure similar tothat described in Example 2, but using 10% palladium on charcoal ascatalyst, as a foam. Rf 0.40 (SS 7). [α]_(D) ²⁵ +65° (c=0.1, CH₃ OH).LRMS: m/z 313.4 (M+1)⁺.

EXAMPLE 155-(4-Hydroxy-1-pent-1-enyl)-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole

Obtained by a procedure similar to that described in Example 1, usingpent-4-en-2-ol as the appropriate alkene, as a solid. Rf 0.15 (SS 7).Found: C,75.64; H,8.74; N,8.51. C₁₉ H₂₆ N₂ O; 0.30 H₂ O requiresC,75.10; H,8.82; N,9.21%.

EXAMPLE 165-(4-Hydroxy-1-pentyl)-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole

Obtained from the title compound of Example 15 by a procedure similar tothat described in Example 2, but using 10% palladium on charcoal ascatalyst, as a foam. Rf 0.16 (SS 7). Found: C,75.18; H,8.91; N,9.07. C₁₉H₂₈ N₂ O; 0.17 H₂ O requires C,75.19; H,9.41; N,9.22%.

EXAMPLE 175-(4-Hydroxy-1-but-1-enyl)-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole

Obtained by a procedure similar to that described in Example 1, usingbut-3-en-1-ol as the appropriate alkene, as a foam. Rf 0.13 (SS 7).[α]_(D) ²⁵ +9° (c=0.1, CH₃ OH). Found: C,75.67; H,8.30; N,9.72. C₁₈ H₂₄N₂ O requires C,76.02; H,8.51; N,9.84%.

EXAMPLE 185-(4-Hydroxy-1-butyl)-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole

Obtained from the title compound of Example 17 by a procedure similar tothat described in Example 2, but using 10% palladium on charcoal ascatalyst, as a foam. Rf 0.14 (SS 7). Found: C,71.04; H,8.27; N,8.61. C₁₈H₂₆ N₂ O; 0.33 CH₂ Cl₂ requires C,70.47; H,8.59; N,8.97%.

EXAMPLE 195-(4-Hydroxy-4-methyl-1-pent-1-enyl)-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole

The title compound was obtained by a procedure similar to that describedin Example 1, using 2-methylpent-4-en-2-ol (J. Chem. Soc. Perkin Trans.II, 1987, 1683) as the appropriate alkene, as a foam. Rf 0.17 (SS 7).Found: C,75.30: H,9.27; N,8.90. C₂₀ H₂₈ N₂ O; 0.33 H₂ O requiresC,75.57; H,9.06; N,8.80%.

EXAMPLE 205-(4-Hydroxy-4-methyl-1-pentyl)-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole

Obtained from the title compound of Example 19 by a procedure similar tothat described in Example 2, but using 10% palladium on charcoal ascatalyst, as a foam. Rf 0.19 (SS 7). Found: C,73.41; H,9.27; N,8.02. C₂₀H₃₀ N₂ O; 0.20 CH₂ Cl₂ requires C,73.19; H,9.24; N,8.44%.

EXAMPLE 215-[3-(1-Hydroxycyclopentyl)-1-prop-1-enyl]-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole

(a) 1-Allylcyclopentanol

Obtained by a procedure similar to that described in the literaturereference of Example 19, using cyclopentanone as the appropriate ketone,as an oil and used without further purification in the following step.

(b)

The title compound was obtained by a procedure similar to that describedin Example 1, using 1-allylcyclopentanol as the appropriate alkene, as asolid. Rf 0.18 (SS 7). [α]_(D) ²⁵ +87° (c=0.1, CH₃ OH). Found: C,77.81;H,8.95; N,8.37. C₂₂ H₃₀ N₂ O requires C,78.06; H,8.93; N,8.27%.

EXAMPLE 225-[3-(1-Hydroxycyclopentyl)-1-propyl]-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole

Obtained from the title compound of Example 21 by a procedure similar tothat described in Example 2, but using 10% palladium on charcoal ascatalyst, as a solid. Rf 0.19 (SS 9). Found: C,70.90; H,8.56; N,7.23.C₂₂ H₃₂ N₂ O; 0.50 CH₂ Cl₂ requires C,70.56; H,8.68; N,7.31%.

EXAMPLE 235-(3-Hydroxy-3-methyl-1-but-1-enyl)-3-(2(R)-pyrrolidinylmethyl)-1H-indole

Obtained from 5-bromo-3-(2(R)-pyrrolidinylmethyl)-1H-indole (Preparation2) and 2-methylbut-3-en-2-ol, by a procedure similar to that describedin Example 1, as a solid. Rf 0.20 (SS 12). [α]_(D) ²⁵ -40° (c=0.1, CH₃OH).

EXAMPLE 243-(N-Cyclopropylmethyl-2(R)-pyrrolidinylmethyl)-5-(3-hydroxy-3-methyl-1-but-1-enyl)-1H-indole

The title compound was preparedby either of the following methods.

(A)

(a) 5-Bromo-3-(N-cyclopropylmethyl-2(R)-pyrrolidinylmethyl)-1H-indole

A stirred mixture of 5-bromo-3-(2(R)-pyrrolidinylmethyl)-1H-indole(Preparation 2; 1.84 g, 6.3 mmol), cyclopropylmethyl bromide (0.67 ml,6.9 mmol), anhydrous sodium carbonate (0.73 g, 6.9 mmol), sodium iodide(1.0 g, 6.7 mmol) and 1,2-dimethoxyethane (10 ml), under nitrogen, washeated under reflux for 14 hours, allowed to cool, then partitionedbetween ethyl acetate and 2M aqueous sodium carbonate solution. Theorganic phase was separated, washed with 2M aqueous sodium carbonatesolution, dried (Na₂ SO₄) and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel, elutingwith 0.880 aqueous ammonia:methanol: dichloromethane (0.05:10:90), toprovide the required product as a foam (2.09 g). Rf 0.24 (SS 6). [α]_(D)²⁵ +72° (c=0.1, CH₃ OH). Found: C,61.22; H,6.40; N,8.39. C₁₇ H₂₁ BrN₂requires C,61.26; H,6.35; N,8.41%.

(b)

The title compound was obtained from the previous product (Example24(A)(a)) by a procedure similar to that described in Example 1, using2-methylbut-3-en-2-ol as the appropriate alkene, as a foam. Rf 0.48 (SS[α]_(D) ²⁵ +59° (c=0.1, CH₃ OH). Found: C,75.52; H,8.66; N,8.00. C₂₂ H₃₀N₂₀ O; 0.17 CH₂ Cl₂ requires C,75.60; H,8.68; N,7.95%.

(B)

The title compound was obtained from the title compound of Example 23and cyclopropylmethyl bromide, by a procedure similar to that describedin Example 24(A)(a), as a solid. Rf 0.44 (SS 7). [α]_(D) ²⁵ +53° (c=0.1,CH₃ OH). Found: C,74.17; H,9.11; N,7.68. C₂₂ H₃₀ N₂ O; 0.125 CH₂ Cl₂ ;0.50 H₂ O requires C,74.21; H,8.79; N,7.82%.

EXAMPLE 253-(N-Cyclopropylmethyl-2(R)-pyrrolidinylmethyl)-5-(3-hydroxy-3-methyl-1-butyl)-1H-indole

Obtained from the title compound of Example 24 by a procedure similar tothat described in Example 2, but using 10% palladium on charcoal ascatalyst and 30 p.s.i. (2.07 bar) hydrogen pressure, as a foam. Rf 0.49(SS 9). Found: C,75.94; H,9.24; N,7.53. C₂₂ H₃₂ N₂ O; 0.15 CH₂ Cl₂requires C,75.31; H,9.21; N,7.92%.

EXAMPLE 265-(3-Hydroxy-3-methyl-1-but-1-enyl)-3-[N-(2-propyl)-2(R)-pyrrolidinylmethyl]-1H-indole

(a) 5-Bromo-3-[N-(2-propyl)-2(R)-pyrrolidinylmethyl]-1H-indole

Obtained by a procedure similar to that described in Example 24(A)(a),using 2-iodopropane as the appropriate alkylating agent, as a foam. Rf0.24 (SS 13). [α]_(D) ²⁵ +66° (c=0.1, CH₃ OH). Found: C,59.81; H,6.99;N,8.50. C₁₆ H₂₁ BrN₂ requires C,59.82; H,6.59; N,8.72%.

(b)

The title compound was obtained from the previous product (Example26(a)) by a procedure similar to that described in Example 1, using2-methylbut-3-en-2-ol as the appropriate alkene, as a foam. Rf 0.07 (SS13). [α]_(D) ²⁵ +56° (c=0.1, CH₃ OH). Found: C,74.67; H,9.49; N,8.09.C₂₁ H₃₀ N₂ O; 0.70 H₂ O requires C,74.38; H,9.33; N,8.26%.

EXAMPLE 275-(3-Hydroxy-3-methl-1-but-1-enyl)-3-[N-(2-methoxyethyl)-2(R)-pyrrolidinylmethyl]-1H-indole

(a) 5-Bromo-3-[N-(2-methoxyethyl)-2(R)-pyrrolidinylmethyl]-1H-indole

Obtained by a procedure similar to that described in Example 24(A)(a),using 2-methoxyethyl bromide as the appropriate alkylating agent, as anoil. Rf 0.45 (SS 11). Found: C,57.25; H,6.41; N,8.14. C₁₆ H₂₁ BrN₂ Orequires C,56.98; H,6.28; N,8.31%.

(b)

The title compound was obtained from the previous product (Example27(a)) by a procedure similar to that described in Example 1, using2-methylbut-3-en-2-ol as the appropriate alkene, as a foam. Rf 0.51 (SS7). [α]_(D) ²⁵ +46° (c=0.1, CH₃ OH). Found: C,67.21; H,8.15; N,7.34. C₂₁H₃₀ N₂ O₂ ; 0.50 CH₂ Cl₂ requires C,67.08; H,8.12; N,7.27%. LRMS: m/z343.5 (M+1)⁺.

EXAMPLE 283-[N-(2-Carbamoylethyl)-2(R)-pyrrolidinylmethyl]-5-(3-hydroxy-3-methyl-1-but-1-enyl)-1H-indole

(a) 5-Bromo-3-[N-(2-carbamoylethyl)-2(R)-pyrrolidinylmethyl]-1H-indole

A stirred mixture of 5-bromo-3-(2(R)-pyrrolidinylmethyl)-1H-indole(Preparation 2; 600 mg, 2.1 mmol), acrylamide (168 mg, 2.4 mmol),triethylamine (0.60 ml) and 1,2-dimethoxyethane (11.9 ml), undernitrogen, was heated under reflux for 8 hours, allowed to cool, thenpartitioned between ethyl acetate (400 ml) and water (400 ml). Theorganic phase was separated, washed with water (400 ml), dried (Na₂ SO₄)and evaporated under reduced pressure. The residue was purified bycolumn chromatography on silica gel, eluting with a solvent gradient of0.880 aqueous ammonia:methanol: dichloromethane (0.1:10:90 to0.4:10:90), to afford the required product as a foam. Rf 0.26 (SS 7).[α]_(D) ²⁵ +59° (c=0.1, CH₃ OH).

(b)

The title compound was obtained from the previous product (Example28(a)) by a procedure similar to that described in Example 1, using2-methylbut-3-en-2-ol as the appropriate alkene, as a white solid. Rf0.08 (SS 7). [α]_(D) ²⁵ +70° (c=0.1, CH₃ OH)- Found: C,67.37; H,8.32;N,10.71. C₂₁ H₂₉ N₃ O₂ ; 0.22 CH₂ Cl₂ ; 0.25 H₂ O requires C,67.32;H,7.97; N,11.10%.

EXAMPLE 295-(3-Hydroxy-3-methyl-1-butyl)-3-(2(R)-pyrrolidinylmethyl)-1H-indole

(a)3-(N-Benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-(3-hydroxy-3-methyl-1-but-1-enyl)-1H-indole

Obtained from3-(N-benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-bromo-1H-indole(Preparation 1) and 2-methylbut-3-en-2-ol, by a procedure similar tothat described in Example 1, as a foam. Rf 0.40 (SS 5). [α]_(D) ²⁵ -10°(c=0.1, CH₃ OH). Found: C,73.72; H6.92; N,6.18. C₂₆ H₃₀ N₂ O₃ ; 0.10 CH₂Cl₂ requires C,73.41; H,7.13; N,6.56%.

(b)

The title compound was obtained from the previous product (Example29(a)) by a procedure similar to that described in Example 2, but using10% palladium on charcoal as catalyst, as a foam. Rf 0.10 (SS 7).[α]_(D) ²⁵ -8° (c=0.1, CH₃ OH). Found: C,70.77; H,8.96; N,9.09. C₁₈ H₂₆N₂ O; H₂ O requires C,71.02; H,9.27; N,9.20%.

EXAMPLE 305-(3-Hydroxy-3-methyl-1-butyl)-3-{N-[2-(4-pyridyl)ethyl]-2(R)-pyrrolidinylmethyl}-1H-indole

Obtained from the title compound of Example 29 and 4-vinylpyridine by aprocedure similar to that described in Example 28(a), except that notriethylamine was used in the reaction, as a foam. Rf 0.18 (SS 13).[α]_(D) ²⁵ +25° (c=0.1, CH₃ OH). Found: C,74.94; H,8.71; N,10.20. C₂₅H₃₃ N₃ O; 0.50 H₂ O requires C,74.96; H,8.56; N,10.49%. LRMS: m/z 392.5(M+1)⁺.

EXAMPLE 313-{N-[2-(Ethylsulphonyl)ethyl]-2(R)-pyrrolidinylmethyl}-5-(3-hydroxy-3-methyl-1-butyl)-1H-indole

Obtained from the title compound of Example 29 and ethyl vinyl sulphone,by a procedure similar to that described in Example 28(a), as a foam. Rf0.42 (SS 13). [α]_(D) ²⁵ +40° (c=0.1, CH₃ OH). Found: C,64.20; H,8.54;N,6.88; S,7.94. C₂₂ H₃₄ N₂ O₃ S; 0.25 H₂ O requires C,64.28; H,8.46;N,6.81; S,7.80%.

EXAMPLE 325-(3-Hydroxy-3-methyl-1-pentyl)-3-(2(R)-pyrrolidinylmethyl)-1H-indole

(a)3-(N-Benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-(3-hydroxy-3-methyl-1-pent-1-enyl)-1H-indole

Obtained from3-(N-benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-bromo-1H-indole(Preparation 1) and 3-methyl-1-penten-3-ol, by a procedure similar tothat described in Example 1, as a foam. Rf 0.90 (SS 7). [α]_(D) ²⁵ -9°(c=0.1, CH₃ OH). Found: C,71.27; H,6.98; N,5.83. C₂₇ H₃₂ N₂ O₃ ; 0.33CH₂ Cl₂ requires C,71.23; H,7.14; N,6.08%.

(b)

The title compound was obtained from the previous product (Example32(a)) by a procedure similar to that described in Example 2, but using10% palladium on charcoal as catalyst, as a foam. Rf 0.10 (SS 7).[α]_(D) ²⁵ -12° (c=0.1, CH₃ OH). Found: C,73.41; H,9.63; N,8.86. C₁₉ H₂₈N₂ O; 0.50 H₂ O requires C,73.74; H,9.44; N,9.05%. LRMS: m/z 301.2(M+1)⁺.

EXAMPLE 335-[2-(1-Hydroxycyclopentyl)ethyl]-3-(2(R)-pyrrolidinylmethyl)-1H-indole

(a)3-(N-Benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-[2-(1-hydroxycyclopentyl)ethenyl]-1H-indole

Obtained by a procedure similar to that described in Example 1, from3-(N-benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-bromo-1H-indole(Preparation 1) and 1-vinylcyclopentanol (Example 5(a)), as a foam. Rf0.40 (SS 10). [α]_(D) ²⁵ -31° (c=0.1, CH₃ OH). Found: C,75.58; H,7.24;N,6.22. C₂₈ H₃₂ N₂ O₃ requires C,75.64; H,7.26; N,6.30%.

(b)

The title compound was prepared from the previous product (Example33(a)) by either of the following methods.

(A)

Obtained by a procedure similar to that described in Example 2, butusing 10% palladium on charcoal as catalyst, as a foam. Rf 0.15 (SS 7).[α]_(D) ²⁵ -13° (c=0.1, CH₃ OH). Found: C,73.32; H,8.89; N,8.51. C₂₀ H₂₈N₂ O; 0.20 CH₂ Cl₂ requires C,73.64; H,8.69; N,8.50%.

(B)

A solution of the title compound of Example 29(a) (290 mg, 0.65 mmol) inethanol (2.5 ml) was added dropwise to a stirred mixture ofpalladium(II) acetate (30 mg, 0.13 mmol), triethylsilane (0.6 ml, 3.8mmol) and triethylamine (0.5 ml, 3.6 mmol) under nitrogen at roomtemperature. After 72 hours, the reaction mixture was filtered, thefiltrate evaporated under reduced pressure and the residue azeotropedwith dichloromethane. Purification of the crude product by columnchromatography on silica gel, eluting with a solvent gradient of 0.880aqueous ammonia:methanol:dichloromethane (0:0:100 to 0:10:90 to1:10:90), afforded the title compound as a foam (125 mg). Rf 0.10 (SS7). [α]_(D) ²⁵ -18° (c=0.1, CH₃ OH). Found: C,74.01; H,9.01; N,8.58. C₂₀H₂₈ N₂ O; 0.06 CH₂ Cl₂ ; 0.33 H₂ O , requires C,74.36; H,8.96; N,8.64%.

EXAMPLE 345-[2-(1-Hydroxycyclopentyl)ethenyl]-3-{N-[2-(N,N-dimethylcarbamoyl)ethyl]-2(R)-pyrrolidinylmethyl}-1H-indole

(a)5-Bromo-3-{N-[2-(N,N-dimethylcarbamoyl)ethyl]-2-(R)-pyrrolidinylmethyl}-1H-indole

Obtained from 5-bromo-3-(2(R)-pyrrolidinylmethyl)1H-indole (Preparation2) and N,N-dimethylacrylamide, by a procedure similar to that describedin Example 28(a), as a foam. Rf 0.58 (SS 7). Found: C,55.53; H,6.18;N,10.66. C₁₈ H₂₄ BrN₃ O; 0.20 CH₂ Cl₂ requires C,55.30; H,6.22;N,10.63%.

(b)

The title compound was obtained from the previous product (Example34(a)) and 1-vinylcyclopentanol (Example 5(a)), by a procedure similarto that described in Example 1, as a foam. Rf 0.40 (SS 7). [α]_(D) ²⁵+27° (c=0.1, CH₃ OH). Found: C,70.55; H,8.74; N,9.47. C₂₅ H₃₅ N₃ O₂ ;0.125 CH₂ Cl₂ ; 0.50 H₂ O requires C,70.31; H,8.51; N,9.79%. LRMS: m/z410.7 (M+1)⁺.

Trituration of a sample with ethyl acetate, followed by crystallisationfrom ethyl acetate, provided a solid, m.p. 151°-152° C. Found: C,73.23;H,8.48; N,9.93. C₂₅ H₃₅ N₃ O₂ requires C,73.31; H,8.61; N,10.23%.

EXAMPLE 355-[2-(1-Hydroxycyclopentyl)ethyl]-3-{N-[2-(N,N-dimethylcarbamoyl)ethyl]-2(R)-pyrrolidinylmethyl}-1H-indole

The title compound was obtained by either of the following methods.

(A)

Obtained from the title compound of Example 33 andN,N-dimethylacrylamide, using a procedure similar to that described inExample 28(a), as a foam. Rf 0.37 (SS 7). [α]_(D) ²⁵ +29° (c=0.1, CH₃OH). Found: C,70.08; H,9.06; N,9.59. C₂₅ H₃₇ N₃ O₂ ; 0.25 CH₂ Cl₂requires C,70.06; H,8.73; N,9.71%.

(B)

Obtained from the title compound of Example 34 by a procedure similar tothat described in Example 2, but using 10% palladium on charcoal ascatalyst, as a foam. [α]_(D) ²⁵ +31° (c=0.1, CH₃ OH). Rf 0.35 (SS 7).Found: C,69.62; H,8.75; N,9.31. C₂₅ H₃₇ N₃ O₂ ; 0.25 CH₂ Cl₂ ; 0.17 H₂ Orequires C,69.58; H,8.75; N,9.64%.

Crystallisation of a sample from ethyl acetate-water provided a solid,m.p. 84°-85° C. Found: C,69.78; H,9.32; N,9.79. C₂₅ H₃₇ N₃ O₂ ; H₂ Orequires C,69.89; H,9.15; N,9.78%. LRMS: m/z 412.0 (M+1)⁺.

The hydrochloride salt was obtained as a solid, m.p. 182°-183° C.(acetone). Rf 0.24 (SS 7). [α]_(D) ²⁵ -52° (c=0.1, CH₃ OH). Found:C,66.00; H,8.65; N,8.98. C₂₅ H₃₇ N₃ O₂ ; HCl requires C,65.70; H,8.49;N,9.19%.

EXAMPLE 365-[2-(1-Hydroxycyclobutyl)ethyl]-3-(2(R)-pyrrolidinylmethyl)-1H-indole

(a)3-(N-Benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-[2-(1-hydroxycyclobutyl)ethenyl]-1H-indole

Obtained from3-(N-benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-bromo-1H-indole(Preparatidn 1) and 1-vinylcyclobutanol (Example 13(a)), by a proceduresimilar to that described in Example 1, as an oil. Rf 0.50 (SS 7).Found: C,68.35; H,6.73; N,5.29. C₂₇ H₃₀ N₂ O₃ ; 0.67 CH₂ Cl₂ requiresC,68.18; H,6.48; N,5.75%.

(b)

The title compound was prepared from the previous product (Example36(a)) by a procedure similar to that described in Example 2, but using10% palladium on charcoal as catalyst, as a foam. Rf 0.11 (SS 4).[α]_(D) ²⁵ -22° (c=0.1, CH₃ OH). Found: C,74.33; H,8.84; N,8.82. C₁₉ H₂₆N₂ O; 0.12 CH₂ Cl₂ requires C,74.41; H,8.57; N,9.08%. LRMS: m/z 299.3(M+1)⁺.

EXAMPLE 37 5-(3-Oxo-1-butyl)-3-(2(R)-pyrrolidinylmethyl)-1H-indole

(a)3-(N-Benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-(3-oxo-1-but-1-enyl)-1H-indole

Obtained by a procedure similar to that described in Example 1, from3-(N-benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-bromo-1H-indole(Preparation 1) and methyl vinyl ketone, as a foam. Rf 0.60 (SS 7).[α]_(D) ²⁵ -51° (c=0.1, CH₃ OH). Found: C,74.16; H,6.39; N,6.92. C₂₅ H₂₆N₂ O₃ requires C,74.60; H,6.51; N,6.96%.

(b)

The title compound was prepared from the previous product (Example37(a)) by a procedure similar to that described in Example 2, but using10% palladium on charcoal as catalyst, as a gum. Rf 0.15 (SS 7). [α]_(D)²⁵ -8° (c=0.1, CH₃ OH). Found: C,69.63; H,7.75; N,9.30. C₁₇ H₂₂ N₂ O;0.17 CH₂ Cl₂ ; 0.67 H₂ O requires C,69.52; H,8.04; N,9.45%.

EXAMPLE 38 5-(3-Hydroxy-1-butyl)-3-(2(R)-pvrrolidinylmethyl)-1H-indole

Sodium borohydride (423 mg, 11 mol) was added portion-wise over 20minutes at room temperature, under nitrogen, to a stirred solution ofthe title compound of Example 37 (1.34 g, 5 mmol) in ethanol (50 ml),then stirring continued for 18 hours. The pH of the resulting reactionmixture was adjusted to 2 with 2N hydrochloric acid, then to 8 withsolid sodium carbonate, and the volume reduced to about half byevaporation under reduced pressure, before partitioning between ethylacetate and water was effected. The organic phase was separated, washedwith water, dried (Na₂ SO₄) and evaporated under reduced pressure togive a foam which was purified by column chromatography on silica gel,eluting with a solvent gradient of 0.880 aqueousammonia:methanol:dichloromethane (0:0:100 to 0:10:90 to 1:10:90 to1.5:15:85), to afford the title compound as a foam. Rf 0.10 (SS 7).[α]_(D) ²⁵ -22° (c=0.1, CH₃ OH). Found: C,72.07; H,8.96; N,9.56. C₁₇ H₂₄N₂ O; 0.10 CH₂ Cl₂ ; 0.17 H₂ O requires C,72.34; H,8.71; N,9.87%.

EXAMPLE 395-(3-Hydroxy-1-butyl)-3-[N-(2-methoxyethyl)-2(R)-pyrrolidinylmethyl]-1H-indole

The title compound was obtained from the title compound of Example 38 bya procedure similar to that described in Example 24(A)(a), using2-methoxyethyl bromide as the appropriate alkylating agent, as a gum. Rf0.30 (SS 7). [α]_(D) ²⁵ +41° (c=0.1, CH₃ OH). Found: C,70.35; H,9.40;N,8.28. C₂₀ H₃₀ N₂ O₂ ; 0.08 CH₂ Cl₂ ; 0.25 H₂ O requires C,70.52;H,9.04; N,8.19%.

EXAMPLE 403-(N-Cyclopropylmethyl-2(R)-pyrrolidinylmethyl)-5-(3-hydroxy-1-butyl)-1H-indole

The title compound was obtained from the title compound of Example 38 bya procedure similar to that described in Example 24(A)(a), usingcyclopropylmethyl bromide as the appropriate alkylating agent, as afoam. Rf 0.40 (SS 7). [α]_(D) ²⁵ +73° (c=0.1, CH₃ OH). Found: C,75.26;H,9.33; N,8.22. C₂₁ H₃₀ N₂ O; 0.50 H₂ O requires C,75.18; H,9.31;N,8.35%.

EXAMPLE 415-(3-Ethyl-3-hydroxy-1-pentyl)-3-(2(R)-pyrrolidinylmethyl)-1H-indole

(a)3-(N-Benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-(3-ethyl-3-hydroxy-1-pent-1-enyl)-1H-indole

Obtained by a procedure similar to that described in Example 1, from3-(N-benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-bromo-1H-indole(Preparation 1) and 3-ethylpent-1-en-3-ol (Example 9(a)), as a foam. Rf0.66 (SS 7). [α]_(D) ²⁵ -27° (c=0.1, CH₃ OH). Found: C,75.33; H,+.29;N,5.65. C₂₈ H₃₄ N₂ O₃ requires C,75.30; H,7.67; N,6.26%.

(b)

The title compound was prepared from the previous product (Example41(a)) by a procedure similar to that described in Example 2, but using10% palladium on charcoal as catalyst, as a foam. Rf 0.12 (SS 7).[α]_(D) ²⁵ -6° (c=0.1, CH₃ OH). Found: C,74.51; H,9.74; N,8.51. C₂₀ H₃₀N₂ O; 0.50 H₂ O requires C,74.26; H,9.66; N,8.66%.

EXAMPLE 42 5-(3-Hydroxy-1-but-1-enyl)-3-(N-methyl-4-piperidyl)-1H-indole

Obtained by a procedure similar to that described in Example 1, using5-bromo-3-(N-methyl-4-piperidyl)-1H-indole (EP-A-0303507) andbut-3-en-2-ol, as a foam. Rf 0.50 (SS 4). Found: C,72.85; H,8.22;N,9.17. C₁₈ H₂₄ N₂ O; 0.17 CH₂ Cl₂ requires C,73.08; H,8.22; N,9.38%.

EXAMPLE 43 5-(3-Hydroxy-1-butyl)-3-(N-methyl-4-piperidyl)-1H-indole

Obtained from the title compound of Example 42 by a procedure similar tothat described in Example 2, but using 10% palladium on charcoal ascatalyst, as a foam. Rf 0.50 (SS 4). C,73.39; H,8.77; N,9.06. C₁₈ H₂₆ N₂O; 0.125 CH₂ Cl₂ requires C,73.28; H,8.91; N,9.43%.

EXAMPLE 445-[2-(1-Hydroxycyclopentyl)ethenyl]-3-(N-methyl-4-piperidyl)-1H-indole

Obtained by analogy with Example 42, using 1-vinylcyclopentanol (Example5(a)) as the appropriate alkene, as a foam. Rf 0.40 (SS 7). [α]_(D) ²⁵-21° (c=0.1, C₃ OH). Found: C,70.70; H,8.19; N,7.31. C₂₁ H₂₈ N₂ O; 0.50CH₂ Cl₂ requires C,70.37; H,7.97; N,7.64%. LRMS: m/z 325 (M+1)⁺.

EXAMPLE 455-[2-(1-Hydroxycyclopentyl)ethyl]-3-(N-methyl-4-piperidyl)-1H-indole

Obtained from the title compound of Example 44, by analogy with Example43. Rf 0.40 (SS 7). Found: C,73.55; H,8.90; N,8.12. C₂₁ H₃₀ N₂ O; 0.25CH₂ Cl₂ requires C,73.44; H,8.85; N,8.06%.

EXAMPLE 465-(3-Hydroxy-3-methyl-1-but-1-enyl-3-(N-methyl-4-piperidyl)-1H-indole

Obtained by analogy with Example 42, using 2-methylbut-3-en-2-ol as theappropriate alkene, as a white solid, m.p 161°-161.5° C. Rf 0.39 (SS 7).Found: C,66.41; H,7.84; N,7.78. C₁₉ H₂₆ N₂ O; 0.67 CH₂ Cl₂ requiresC,66.49; H,7.75; N,7.88%. LRMS: m/z 299.2 (M+1)⁺.

EXAMPLE 47 3-(2-Aminoethyl)-5-(3-hydroxy-3-methyl-1-but-1-enyl)-1H-indole

(a) 5-(3-Hydroxy-3-methyl-1-but-1-enyl)-3-(2-phthalimidoethyl)-1H-indole

Obtained by a procedure similar to that described in Example 1, using5-bromo-3-(2-phthalimidoethyl)-1H-indole (which was prepared asdescribed in U.S. Pat. No. 4,252,803) and 2-methylbut-3-en-2-ol, as afoam. Rf 0.10 (SS 8). Found: C,72.31; H,6.09; N,.7.16. C₂₃ H₂₂ N₂ O₃ ;0.15 CH₂ Cl₂ requires C,71.82; H,5.81; N,7.23%.

(b)

A solution of hydrazine hydrate (0.5 ml) in ethanol (20 ml) was added,under nitrogen, to a stirred solution of the previous product (Example47(a); 0.864 g, 2.3 mmol) in ethanol (5 ml) at room temperature, thenthe resulting solution heated under reflux for 24 hours, allowed to cooland evaporated under reduced pressure. The residue was dissolved inethyl acetate and this solution washed sequentially with 10% aqueoussodium carbonate solution (×4) and brine, dried (Na₂ SO₄) and evaporatedunder reduced pressure to provide an oil which, on azeotroping withdichloromethane, followed by purification of the resulting foam bycolumn chromatography using 0.880 aqueousammonia:ethanol:dichloromethane (1:8:25) as eluant, furnished the titlecompound as a white foam (250 mg). Rf 0.30 (SS 4). Found: C,71.52;H,8.15; N,11.06. C₁₅ H₂₀ N₂ O; 0.10 CH₂ Cl₂ ; requires C,71.73; H,8.05;N,11.08%.

EXAMPLE 48 3-(2-Aminoethyl)-5-(3-hydroxy-3-methyl-1-butyl)-1H-indole

Obtained from the title compound of Example 47, by a procedure similarto that described in Example 2, as a white foam. Rf 0.30 (SS 4). Found:C,70.77; H,8.78; N,10.71. C₁₅ H₂₂ N₂ O; 0.05 CH₂ Cl₂ ; 0.25 H₂ Orequires C,70.86; H,8.92; N,10.98%.

EXAMPLE 493-(N-Methyl-2(R)-pyrrolidinylmethyl)-5-(3-oxo-1-but-1-enyl)-1H-indole

Obtained by a procedure similar to that described in Example 1, usingmethyl vinyl ketone as the appropriate alkene, as a foam. Rf 0.38 (SS7). [α]_(D) ²⁵ +99° (C=0.1, CH₃ OH). Found: C,71.97; H,7.71; N,9.34. C₁₈H₂₂ N₂ O; 0.10 CH₂ Cl₂ ; 0.50 H₂ O requires C,72.15; H,7.86; N,9.35%.

EXAMPLE 503-(N-Methyl-2(R)-pyrrolidinylmethyl)-5-(3-oxo-1-butyl)-1H-indole

Obtained from the title compound of Example 49 by a procedure similar tothat described in Example 2, but using 10% palladium on charcoal ascatalyst, as a foam. [α]_(D) ²⁵ +83° (c=0.1, CH₃ OH). Found: C,71.61;H,8.36; N,9.02. C₁₈ H₂₄ N₂ O; 0.20 CH₂ Cl₂ requires C,71.84; H,8.16;N,9.30%. LRMS: m/z 285.3 (M+1)⁺.

EXAMPLE 513-(N-Methyl-2(R)-pyrrolidinylmethyl)-5-(3-oxo-1-pent-1-enyl)-1H-indole

Obtained by a procedure similar to that described in Example 1, usingethyl vinyl ketone as the appropriate alkene, as a foam. Rf 0.70 (SS 7).[α]_(D) ²⁵ +115° (c=0.1, CH₃ OH). Found: C,74.85; H,8.22; N,9.47. C₁₉H₂₄ N_(O) ; 0.10 CH₂ Cl₂ requires C,75.24; H,7.99; N,9.19%.

EXAMPLE 523-(N-Methyl-2(R)-pyrrolidinylmethyl)-5-(3-oxo-1-pentyl)-1H-indole

Obtained from the title compound of Example 51 by a procedure similar tothat described in Example 2, but using 10% palladium on charcoal ascatalyst, as a gum. Rf 0.70 (SS 7). [α]_(D) ²⁵ +105° (c=0.1, C₃ OH).Found: C,73.04; H,8.66; N,8.97. C₁₉ H₂₆ N₂ O; 0.75 H₂ O requiresC,73.15; H,8.88; N,8.98%.

EXAMPLE 53 5-Acetyl-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole

The first step was conducted under Heck reaction conditions similar tothose described in Example 1, using ethyl vinyl ether as the appropriatealkene.

The crude intermediate,5-(1-ethoxyethenyl)-3-(N-methyl-2(R)-pyrroldinylmethyl)-1H-indole, wasdissolved in 2M hydrochloric acid and the resulting solution stirred for0.5 hour at room temperature, then basified to pH 9 with 10% aqueoussodium carbonate solution. Extraction with ethyl acetate (×3), followedby drying (Na₂ SO₄) and evaporation under reduced pressure of thecombined extracts, gave the crude product which was purified by columnchromatography on silica gel, eluting with 0.880 aqueousammonia:methanol:dichloromethane (1:12.5:86.5), to afford the titlecompound. Rf 0.30 (SS 15). Found: C,74.08; H,8.11; N,10.81. C₁₆ H₂₀ N₂O; 0.17 CH₂ Cl₂ requires C,73.73; H,7.75; N,10.71%.

EXAMPLE 54 3-(N-Methy1-4-piperidyl)-5-(3-oxo-1-pent-1-enyl)-1H-indolehydrobromide

Obtained by analogy with Example 42, using ethyl vinyl ketone as theappropriate alkene, but avoiding treatment with aqueous base duringreaction work-up. Instead, the resulting reaction mixture was evaporatedunder reduced pressure to provide the crude product which was thenpurified, as usual, by column chromatography on silica gel to furnishthe title compound. Rf 0.70 (SS 4). Found: C,58.15; H,6.60; N,7.18. C₁₉H₂₄ N₂ O; HBr; 0.25 CH₂ Cl₂ requires C,58.01; H,6.45; N,7.03%.

EXAMPLE 55 3-(N-Methyl-4-piperidyl)-5-(3-oxo-1-pentyl)-1H-indole

Obtained from the title compound of Example 54 by a procedure similar tothat described in Example 2, but using 10% palladium on charcoal ascatalyst. The use of diethylamine:ethyl acetate:hexane (5:25:70) aseluant in the column chromatography on silica gel purification procedureafforded the title compound as the free base. Rf 0.08 (SS 14). Found:C,76.05; H,8.61; N,8.81. C₁₉ H₂₆ N₂ O; 0.05 CH₂ Cl₂ ; 0.06 (C₂ H₅)₂ NHrequires C,76.47; H,8.78; N,9.39%.

EXAMPLE 56 5-(1-Hydroxyethyl)-3-(N-methyl-4-piperidyl)-1H-indole

A 1.7M solution of t-butyllithium in hexane (8.03 ml, 13.65 mmol) wasadded dropwise, under nitrogen, to a stirred solution of5-bromo-3-(N-methyl-4-piperidyl)-1H-indole (EP-A-0303507, 1.0 g, 3.4mmol) in dry tetrahydrofuran (35 ml) at about -70° C., ensuring that thetemperature of the reaction mixture did not rise above -50° C. duringthe addition. The resulting mixture was allowed to warm to roomtemperature over a period of 1 hour, then cooled to about -70° C. andtreated, dropwise, with a solution of acetaldehyde (0.15 g, 3.4 mmol) indry tetrahydrofuran (5 ml). After being stirred for a further 0.5 hourat about -70° C., the reaction mixture was quenched with water andallowed to warm to room temperature. The bulk of the organic solventswas removed by evaporation under reduced pressure and the remainingmixture partitioned between ethyl acetate and 10% aqueous ammoniumchloride solution. The organic phase was separated, combined with twofurther ethyl acetate extracts of the aqueous phase, dried (Na₂ SO₄) andevaporated under reduced pressure to give an oil which was purified bycolumn chromatography on silica gel, eluting with 0.880 aqueousammonia:methanol:dichloromethane (1:20:79), to provide the titlecompound which was employed in the following Example without furthercharacterisation.

EXAMPLE 57 5-Acetyl-3-(N-methyl-4-piperidyl)-1H-indole

A mixture of the title compound of Example 56 (160 mg, 0.62 mmol),activated manganese dioxide (1.6 g), dichloromethane (12 ml) andacetonitrile (3 ml) was stirred for 16 hours at room temperature, when afurther portion of activated manganese dioxide (0.6 g) was added. Aftera further 4 days, the reaction mixture was filtered and the filtrateevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel, eluting with 0.880 aqueousammonia:methanol:dichloromethane (1:12:5:86.5), to afford the titlecompound (35 mg). Rf 0.35 (SS 15). Found: C,73.30; H,7.76; N,10.65. C₁₆H₂₀ N₂ O; 0.17 CH₂ Cl₂ requires C,73.73; H,7.75; N,10.71%.

EXAMPLE 585-(3-Hydroxy-3-methyl-1-butyl)-3-[N-(2-methoxyethyl)-2(R)-pyrrolidinylmethyl]-1H-indole

Obtained from the title compound of Example 27 by a procedure similar tothat described in Example 2, but using 10% palladium on charcoal ascatalyst, as a gum. Rf 0.50 (SS 7). [α]_(D) ²⁵ +64° (c=0.1, CH₃ OH).LRMS: m/z 345.7 (M+1)⁺.

EXAMPLE 595-(3-Hydroxy-3-methyl-1-butyl)-3-[N-(2-propyl)-2(R)-pyrrolidinylmethyl]-1H-indole

The title compound was obtained by either of the following methods.

(A)

Obtained from the title compound of Example 26 by a procedure similar tothat described in Example2, but using 10% palladium on charcoal ascatalyst, as a foam. Rf 0.17 (SS 7). [α]_(D) ²⁵ +24° (c=0.1, CH₃ OH).LRMS: m/z 329.8 (M+1)⁺.

(B)

Obtained from the title compound of Example 29 and 2-iodopropane by aprocedure similar to that described in Example 24(A)(a), but in thepresence of 4-dimethylaminopyridine (0.05 equiv), as a foam. Rf 0.24 (SS13). [α]_(D) ²⁵ +16° (c=0.1, CH₃ OH). Found: C,70.62; H,9.27; N,7.92.C₂₁ H₃₂ N₂ O; 0.42 CH₂ Cl₂ requires C,70.69; H,9.09; N,7.70%.

EXAMPLE 605-[2-Hydroxycyclopentyl)ethyl]-3-[N-(2-hydroxyethyl)-2(R)-pyrrolidinylmethyl]-1H-indole

A stirred mixture of the title compound of Example 33 (400 mg, 1.3mmol), ethylene carbonate (124 mg, 1.4 mmol) and dimethylformamide (6ml) was heated at 100°-120° C. under nitrogen for 48 hours, allowed tocool, then partitioned between ethyl acetate and water. The organicphase was separated, washed with water, dried (Na₂ SO₄) and evaporatedunder reduced pressure to furnish an oil (480 mg) which was purified bycolumn chromatography on silica gel, eluting with a solvent gradient of0.880 aqueous ammonia:methanol:dichloromethane (0:0:100 to 0:10:90 to1:10:90), to give the title compound as a foam. Rf 0.50 (SS 7). [α]_(D)²⁵ +55° (c=0.1, CH₃ OH). Found: C,72.60; H,9.34; N,7.58. C₂₂ H₃₂ N₂ O₂ ;0.50 H₂ O requires C,72.29; H,9.10; N,7.67%. LRMS: m/z 357.4 (M+1)⁺.

EXAMPLE 615-(3-Hydroxy-3-methyl-1-butyl)-3-[N-(2-hydroxy-2-methylpropyl)-2(R)-pyrrolidinylmethyl]-1H-indole

A stirred solution of the title compound of Example 29 (400 mg, 1.4mmol), 2,2-dimethyloxirane (0.19 ml, 2.1 mmol) and triethylamine (0.51ml) in 1,2-dimethoxyethane (10 ml) was heated under reflux undernitrogen for 24 hours. Further quantities of 2,2-dimethyloxirane (0.19ml, 2.1 mmol) and triethylamine (0.25 ml) were added, heating underreflux continued for a further 68 hours, the same quantities of reagentsagain added to the reaction mixture, and heating under reflux continuedfor a further 42 hours, before evaporation under reduced pressure waseffected. The residue was partitioned between ethyl acetate and 2Maqueous sodium carbonate solution, then the aqueous phase extracted withethyl acetate. The combined ethyl acetate solutions were dried (Na₂ SO₄)and evaporated under reduced pressure, then the residue purified bycolumn chromatography on silica gel, eluting with 0.880 aqueousammonia:methanol:dichloromethane (0.1:5:95), to afford the titlecompound as a foam. [α]_(D) ²⁵ +58° (c=0.1, CH₃ OH). Found: C,72.88;H,9.62; N,7.54. C₂₂ H₃₄ N₂ O₂ ; 0.25 H₂ O requires C,72.79; H,9.58;N,7.72%. LRMS: m/z 359.5 (M+1)⁺.

EXAMPLE 625-[2-(1-Hydroxycyclopentyl)ethyl]-3-[N-(N-methylcarbamoylmethyl)-2(R)-pyrrolidinylmethyl]-1H-indole

(a) N-Methyl-2-bromoacetamide

A solution of α-bromoacetyl bromide (12.5 ml, 140 mmol) indichloromethane (17.5 ml) was added dropwise over 1.5 hours to a stirredmixture of 25/30% w/v aqueous methylamine solution (12.5 ml), 6.25Maqueous sodium hydroxide solution (25 ml) and dichloromethane (105 ml)at -10° C. After a further 0.5 hour, the cooling bath was removed andthe reaction mixture stirred at room temperature for 2 hours. Theorganic phase was separated, combined with a dichloromethane extract ofthe aqueous phase, washed with saturated brine, dried (NaSO₄) andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel, eluting with a solvent gradient of ethylacetate:hexane (0:100 to 70:30), to give the required amide (12.5 g) asa foam. Rf 0.45 (SS 17). δ(CDCl₃): 2.90(3H,d), 3.92(2H,s),6.30-6.70.(1H,br s).

(b)

The title compound was prepared from the previous product (Example62(a)) and the title compound of Example 33, by a procedure similar tothat described in Example 24(A)(a), as a foam. Rf 0.50 (SS 7). [α]_(D)²⁵ +5° (c=0.1, CH₃ OH). Found: C,71.68; H,8.77; N,10.73. C₂₃ H₃₃ N₃ O₂requires C,72.02; H,8.67; N,10.96%. LRMS: m/z 384.3 (M+1)⁺.

EXAMPLE 633-[N-(2-Carbamoylethyl)-2(R)-pyrrolidinylmethyl]-5-(3-hydroxy-3-methyl-1-butyl)-1H-indole

Obtained from the title compound of Example 28 by a procedure similar tothat.described in Example 2, but using 10% palladium on charcoal ascatalyst, as a foam. Rf 0.25 (SS 7). [α]_(D) ²⁵ +61° (c=0.1, CH₃ OH).Found: C,67.28; H,8.75; N,10.94. C₂₁ H₃₁ N₃ O₂ ; H₂ O requires C,67.17;H,8.86; N,11.19%. LRMS: m/z 358.2 (M+1)⁺.

EXAMPLE 645-[2-(1-Hydroxycyclopentyl)ethyl]-3-{N-[2-(N-methylcarbamoyl)ethyl]-2(R)-pyrrolidinylmethyl}-1H-indole

(a) N-Methylacrylamide

N,N-Diisopropylethylamine (57.8 ml, 331 mmol) was added to a stirred,ice-cooled solution of acryloyl chloride (15 g, 165.7 mmol) in anhydrousdichloromethane (200 ml) followed, portionwise, by methylaminehydrochloride (11.19 g, 165.7 mmol) so as to maintain the internaltemperature of the reaction mixture below 5° C. The reaction mixture wasallowed to warm to room temperature, then washed twice with water (100,then 150 ml). The combined aqueous washings were saturated with sodiumchloride and exhaustively extracted with dichloromethane (×7), then thedichloromethane extracts and reaction solution were combined, dried (Na₂SO₄) and evaporated under reduced pressure. The residual solid waspurified by column chromatography on silica gel, eluting with a solventgradient of ethyl acetate:hexane (0:100 to 100:0), to provide therequired amide as an oil. Rf 0.10 (SS 10) δ(CDCl₃): 2.88 (3H, d), 5.60(1H, d), 5.95-6.30 (3H, m).

(b)

The title compound was prepared from the previous product (Example 64(a)and the title compound of Example 33 by a procedure similar to thatdescribed in Example 28(a), as a foam. Rf 0.40 (SS 7). [α]_(D) ²⁵ +37°(c=0.1, CH₃ OH). Found: C,70.81; H,8.81; N,10.17. C₂₄ H₃₅ N₃ O₂ ; 0.14CH₂ Cl₂ requires C,70.71; H,8.68; N,10.26%.

EXAMPLE 655-(3-Hydroxy-3-methyl-1-but-1-enyl)-3-{N-[2-(N-methylcarbamoyl)ethyl]-2(R)-pyrrolidinylmethyl}-1H-indole

(a)5-Bromo-3-{N-[2-(N-methylcarbamoyl)ethyl]-2(R)-pyrrolidinylmethyl}-1H-indole

Obtained from the products of Preparation 2 and Example 64(a), by aprocedure similar to that described in Example 28(a), as a foam. Rf 0.54(SS 7). [α]_(D) ²⁵ +66° (c=0.1, CH₃ OH). Found: C,55.53; H,5.96;N,11.42. C₁₇ H₂₂ BrN₃ O requires C,56.05; H,6.09; N,11.53%. LRMS: m/z364.0 (⁷⁹ Br M+1)⁺ and 366.3 (⁸¹ Br M+1)⁺.

(b)

The title compound was prepared from the previous product (Example65(a)) by a procedure similar to that described in Example 1, using2-methylbut-3-en-2-ol as the appropriate alkene, as a foam. Rf 0.18 (SS7). [α]_(D) ²⁵ +43° (c=0.1, CH₃ OH). Found: C,67.85; H,8.56; N,10.20.C₂₂ H₃₁ N₃ O₂ ; 0.33 CH₂ Cl₂ requires C,67.81; H,8.06; N,10.63%.

EXAMPLE 665-(3-Hydroxy-3-methyl-1-butyl)-3-{N-[2-(N-methylcarbomoyl)ethyl]-2(R)-pyrrrolidinylmethyl}-1H-indole

The title compound was obtained by either of the following methods.

(A)

Obtained from the title compound of Example 65 by using a proceduresimilar to that described in Example 2, but using 10% palladium oncharcoal as catalyst at 30 p.s.i. (2.07 bar) hydrogen pressure, as afoam. Rf 0.35 (SS 7). [α]_(D) ²⁵ 41° (c=0.1, CH₃ OH). LRMS: m/z 372.2(M+1)⁺.

(B)

Obtained from the title compound of Example 29 and N-methylacrylamide(Example 64(a)), by a procedure similar to that described in Example28(a), as a foam. Rf 0.05 (SS 13). [α]_(D) ²⁵ +58° (c=0.1, CH₃ OH).Found: C,69.91; H,8.97; N,10.61. C₂₂ H₃₃ N₃ O₂ ; 0.125 CH₂ Cl₂ requiresC,69.54; H,8.77; N,11.00%. LRMS: m/z 372.3 (M+1)⁺.

EXAMPLE 675-(3-Hydroxy-3-methyl-1-but-1-enyl)-3-{N-[2-(N,N-dimethylcarbamoyl)ethyl]-2(R)-pyrrolidinylmethyl}-1H-indole

Obtained from the product of Example 34(a) and 2-methylbut-3-en-2-ol, bya procedure similar to that described in Example 1, as a foam. Rf 0.37(SS 7). [α]_(D) ²⁵ +21° (c=0.1, CH₃ OH). Found: C,70.68; H,8.66;N,10.38. C₂₃ H₃₃ N₃ O₂ ; 0.11 CH₂ Cl₂ requires C,70.65; H,8.52;N,10.69%.

EXAMPLE 685-(3-Hydroxy-3-methyl-1-butyl)-3-{N-[2-(N,N-dimethylcarbamoyl)ethyl]-2(R)-pyrrolidinylmethyl}-1H-indole

The title compound was obtained by either of the following methods.

(A)

Obtained from the title compound of Example 67 by a procedure similar tothat described in Example 2, using 10% palladium on charcoal as acatalyst, as a foam. Rf 0.39 (SS 7). [α]_(D) ²⁵ +12° (c=0.1, CH₃ OH).Found: C,68.09; H,9.21; N,10.38. C₂₃ H₃₅ N₃ O₂ ; 0.10 CH₂ Cl₂ ; 0.67 H₂O requires C,68.33; H,9.04; N,10.35%.

(B)

Obtained from the title.compound of Example 29 andN,N-dimethylacrylamide, by a procedure similar to that described inExample 28(a), as a foam. [α]_(D) ²⁵ +41° (c=0.1, CH₃ OH). Found:C,69.62; H,8.98; N,10.26. C₂₃ H₃₅ N₃ O₂ ; 0.70 H₂ O requires C,69.37;H,9.22; N,10.55%. LRMS: m/z 384.3 (M+1)⁺.

EXAMPLE 693-{N-[2-(N,N-Dimethylcarbamoyl)ethyl]-2(R)-pyrrolidinylmethyl}-5-(3-oxo-1-but-1-enyl)-1H-indole

Obtained from the product of Example 34(a) and methyl vinyl ketone, by aprocedure similar to that described in Example 1, as a gum. Rf 0.50 (SS7). [α]_(D) ²⁵ +42° (c=0.1, CH₃ OH). Found: C,68.80; H,8.09; N,11.04.C₂₂ H₂₉ N₃ O₂ ; 0.10 CH₂ Cl₂ ; 0.50 H₂ O requires C,68.95; H,7.91;N,10.92%.

EXAMPLE 703-{N-[2-(N,N-Dimethylcarbamoyl)ethyl]-2(R)-pyrrolidinylmethyl}-5-(3-oxo-1-butyl)-1H-indole

Obtained from the title compound of Example 69 by a procedure similar tothat described in Example 2, but using 10% palladium on charcoal ascatalyst, as a gum. Rf 0.35 (SS 7). [α]_(D) ²⁵ +82° (c=0.1, CH₃ OH).LRMS: m/z 370.6 (M+1)⁺.

EXAMPLE 715-(3-Hydroxy-1-butyl)-3-{N-[2-(N,N-dimethylcarbamoyl)-ethyl]-2(R)-pyrrolidinylmethyl}-1H-indole

Obtained from the title compound of Example 70, by a procedure similarto that described in Example 38, as a foam. Rf 0.28 (SS 7). [α]_(D) ²⁵+51° (c=0.1, CH₃ OH). Found: C,69.12; H,9.34; N,10.93. C₂₂ H₃₃ N₃ O₂ ;0.67 requires C,68.90; H,9.02; N,10.96%. LRMS: m/z 372.2 (M+1)⁺.

EXAMPLE 725-(3-Hydroxy-3-methyl-1-butyl)-3-{N-[2-(N,N-dimethylcarbamoyl)-1-propyl]-2(R)-pyrrolidinylmethyl}-1H-indole

A stirred solution of the title compound of Example 29 (400 mg, 1.4mmol) and N,N-dimethylmethacrylamide (174 mg, 1.5 mmol) in pyridine (2ml), under nitrogen, was heated under reflux for 61 hours, then afurther quantity of N,N-dimethylmethylacrylamide (315 mg, 2.8 mmol) wasadded to the reaction mixture. After a further 91 hours under reflux,the cool reaction mixture was diluted with ethyl acetate and then washedtwice with 2M aqueous sodium carbonate solution. The combined aqueouswashings were extracted with ethyl acetate, then the combined organicsolutions dried (Na₂ SO₄) and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel, elutingwith 0.880 aqueous ammonia:methanol: dichloromethane (0.5:5:95), tofurnish the title compound as a single diastereoisomer. [α]_(D) ²⁵ +50°(c=0.1, CH₃ OH). Found: C,70.59; H,9.02; N,9.94. C₂₄ H₃₇ N₃ O₂ ; 0.15CH₂ Cl₂ requires C,70.35; H,9.12; N,10.19%. LRMS: m/z 400.3 (M+1)⁺.

EXAMPLE 735-(3-Hydroxy-3-methyl-1-butyl)-3-{N-[2-(N-methylcarbamoyl)-1-propyl]-2(R)-pyrrolidinylmethyl}-1H-indole

Obtained from the title compound of Example 29 andN-methylmethacrylamide, by a procedure similar to that described inExample 72, as a mixture of diastereoisomers which were separated bychromatography on silica gel, eluting with 0.880 aqueous ammonia:methanol:dichloromethane (0:1:5:95).

Diastereoisomer A

Foam. Rf 0.39 (SS 7). [α]_(D) ²⁵ +55° (c=0.1, CH₃ OH). Found: C,68.97;H,9.04; .N,10.12. C₂₃ H₃₅ N₃ O₂ ; 0.225 CH₂ Cl₂ requires C,68.93;H,8.83; N,10.38%. LRMS: m/z 386.3 (M+1)⁺.

Diastereoisomer B

Foam. Rf 0.32 (SS 7). [α]_(D) ²⁵ +6° (c=0.1, CH₃ OH). Found: C,68.70;H,9.00; N,10.12. C₂₃ H₃₅ N₃ O₂ ; 0.25 CH₂ Cl₂ requires C,68.65; H,8.80;N,10.33%.

EXAMPLE 745-[2-(1-Hydroxycyclopentyl)ethyl]-3-[N-(2-morpholinocarbonylethyl)-2(R)-pyrrolidinylmethyl]-1H-indole

Obtained from the title compound of Example 33 and N-acryloylmorpholine,by a procedure similar to that described in Example 28(a), as a foam. Rf0.46 (SS 7). [α]_(D) ²⁵ +24° (c=0.1, CH₃ OH). Found: C,67.91; H,8.72;N,8.57. C₂₇ H₃₉ N₃ O₃ ; 0.33 CH₂ Cl₂ ; 0.10 H₂ O requires C,68.17;H,8.34; N,8.73%. LRMS: m/z 454.3 (M+1)⁺.

EXAMPLE 755-[2-(1-Hydroxycyclopentyl)ethyl]-3-{N-[2-(N-2-methoxyethylcarbomoyl)ethyl]-2(R)-pyrrolidinylmethyl}-1H-indole

(a) N-(2-Methoxyethyl)acrylamide

N,N-Diisopropylethylamine (3.21 g, 25 mmol) was added to a stirred,ice-cooled solution of acryloyl chloride (2.25 g, 25 mmol) indichloromethane (30 ml) under nitrogen followed, 2 minutes later, by2-methoxyethylamine (1.92 g, 25.6 mmol) added dropwise over 1 hour. Thecooling bath was removed, then the reaction mixture stirred for 18 hoursat room temperature and washed twice with water. The combined aqueouswashings were saturated with sodium chloride and exhaustively extractedwith dichloromethane. All the dichloromethane solutions were combined,washed twice with 2M aqueous sodium carbonate solution, dried (Na₂ SO₄)and evaporated under reduced pressure. The residue was purified bycolumn chromatography on silica gel, eluting with a solvent gradient ofethanol: dichloromethane (0:100 to 5:95), to yield the required amide asan oil. Rf 0.63 (SS 7). Found: C,54.97; H,9.24; N,10.68. C₆ H₁₁ NO₂ ;0.10 H₂ O requires C,55.04; H,8.62; N,10.70%. LRMS: m/z 130.4 (M+1)⁺.

(b)

The title compound was obtained from the title compound of Example 33and the previous product (Example 75(a)), by a procedure similar to thatdescribed in Example 28(a), as a foam. Rf 0.44 (SS 7). [α]_(D) ²⁵ +42°(c=0.1, CH₃ OH). Found: C,68.59; H,9.02; N,9.11. C₂₆ H₃₉ N₃ O₃ ; H₂ Orequires C,68.61; H,8.96; N,9.23%. LRMS: m/z 442.4 (M+1)⁺.

EXAMPLE 763-{N-[2-(N-2-Benzyloxyethylcarbamoyl)ethyl]-2(R)-pyrrolidinylmethyl}-5-[2-(1-hydroxycyclopentyl)ethyl]-1H-indole

(a) N-(2-Benzyloxyethyl)acetamide

A solution of N-acetylethanolamine (10.0 g, 6.79 ml, 97 mmol) in amixture of anhydrous tetrahydrofuran (100 ml) and dimethylformamide (10ml) was added to a stirred suspension of 80% sodium hydride in oildispersion (2.90 g, 97 mmol) in dry tetrahydrofuran (140 ml), undernitrogen, at room temperature. After 1 hour, the reaction mixture washeated to 40°-50° C. and then, after a further 0.5 hour, cooled toice-bath temperature. Next, benzyl bromide (13.8 ml, 116 mmol) was addedand the resulting suspension stirred at room temperature for 18 hours,before being cautiously quenched with water (400 ml). The resultingmixture was extracted with ethyl acetate (2×300 ml) and the combinedextracts washed with water (200 ml), dried (Na₂ SO₄) and evaporatedunder reduced pressure. The resulting residue was partitioned betweenethyl acetate and water, then the organic phase washed thrice withwater, dried (Na₂ SO₄) and evaporated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel, elutingwith a solvent gradient of methanol:ethyl acetate (0:100 to 10:90), togive the required product (7.8 g) as an oil. Rf 0.21 (SS 17). LRMS: m/z194.3 (M+1)⁺.

(b) 2-Benzyloxyethylamine

6M Hydrochloric acid (60 ml) was added to a stirred solution of theprevious product (Example 76(a); 7.80 g, 40 mmol) in methanol (125 ml)and the resulting mixture heated under reflux for 48 hours, thenevaporated under reduced pressure. The residue was partitioned betweenethyl acetate and water, and the pH of the separated aqueous phaseadjusted to neutrality with 2M aqueous sodium hydroxide solution. Theaqueous phase was exhaustively extracted with ethyl acetate and thecombined extracts dried (Na₂ SO₄) and evaporated under reduced pressureto provide the required amine as an oil. Rf 0.16 (SS 7). LRMS: m/z 152.4(M+1)⁺.

(c) N-Acryloyl-2-benzyloxyethylamine

Obtained from the previous product (Example 76(b)) and acryloylchloride, by a procedure similar to that described in Example 75(a), asan oil. Rf 0.68 (SS 7). Found: C,68.94; H,7.13; N,6.42. C₁₂ H₁₅ NO₂ ;0.06 CH₂ Cl₂ requires C,68.83; H,7.24; N,6.65%. LRMS: m/z 206.1 (M+1)⁺.

(d)

The title compound was obtained from the title compound of Example 33and the previous product (Example 76(c)), by a procedure similar to thatdescribed in Example 28(a), as a foam. Rf 0.42 (SS 7). [α]_(D) ²⁵ +30°(c=0.1, CH₃ OH). Found: C,73.23; H,8.36; N,7.99. C₃₂ H₄₃ N₃ O; 0.10 CH₂Cl₂ requires C,73.26; H,8.27; N,7.98%. LRMS: m/z 519.0 (M+1)⁺.

EXAMPLE 775-[2-(1-Hydroxycyclopentyl)ethyl]-3-{N-[2-(N-2-hydroxyethylcarbamoyl)ethyl]-2(R)-pyrrolidinylmethyl}-1H-indole

Obtained from the title compound of Example 76 by a procedure similar tothat described in Example 2, but using 10% palladium on charcoal as acatalyst, as a foam. Rf 0.19 (SS 7). [α]_(D) ²⁵ +41° (c=0.1, CH₃ OH).Found: C,67.50; H,8.40; N,8.96. C₂₅ H₃₇ N₃ O₃ ; 0.17 CH₂ Cl₂ requiresC,67.05; H,8.46; N,9.32%. LRMS: m/z 428.8 (M+1)⁺.

EXAMPLE 785-[2-(1-Hydroxycyclopentyl)ethyl]-3-{N-[2-(N,N-dimethylcarbamoylmethyl]carbamoyl)ethyl]-2(R)-pyrrolidinylmethyl}-1H-indole

(a) N-Benzyloxycarbonylglycine dimethylamide

Obtained from N-benzyloxycarbonylglycine and dimethylaminehydrochloride, by a "peptide coupling procedure" similar to thatdescribed in Example 81(b), as an oil. Rf 0.35 (SS 20). Found: C,60.76;H,6.93; N,11.62. C₁₂ H₁₆ N₂ O₃ requires C,61.00; H,6.83; N,11.86%. LRMS:m/z 237.0 (M+1)⁺.

(b) Glycine dimethylamide

Obtained from the previous product (Example 78(a)) by a proceduresimilar to that described in Example 2, but using 10% palladium oncharcoal as catalyst, as an oil. Rf 0.21 (SS 7). LRMS: m/z 103.1 (M+1)⁺.HRMS: m/z 103.08710.

(c) N-Acryloylglycine dimethylamide

Obtained from the previous product (Example 78(b)) and acryloylchloride, by a procedure similar to that described in Example 75(a), asa solid, m.p. 74°-75° C. Rf 0.61 (SS 7). Found: C,53.84; H,7.86;N,17.58. C₇ H₁₂ N₂ O₂ requires C,53.83; H,7.74; N,17.94%. LRMS: m/z157.2 (M+1)⁺.

(d)

The title compound was obtained from the previous product (Example78(c)) and the title compound of Example 33, by a procedure similar tothat described in Example 28(a), as a foam. Rf 0.21 (SS 7). [α]_(D) ²⁵+40° (c=0.1, CH₃ OH). Found: C,65.44; H,8.42; N,10.78. C₂₇ H₄₀ N₄ O₃ ;0.33 CH₂ Cl₂ ; 0.50 H₂ O requires C,65.16; H,8.33; N,11.13%. LRMS: m/z469.7 (M+1)⁺.

EXAMPLE 795-[2-(1-Hydroxycyclopentyl)ethyl]-3-{N-[2-(N-[2-(N,N-dimethylcarbomoyl)ethyl]carbamoyl)ethyl]-2(R)-pyrrolidinylmethyl}-1H-indole

(a) N-Benzyloxycarbonyl-B-alanine dimethylamide

Obtained from N-benzyloxycarbonyl-B-alanine and dimethylaminehydrochloride, by a procedure similar to that described in Example 81(b), as an oil. Rf 0.51 (SS 7). LRMS: m/z 251.3 (M+1)⁺.

(b) B-Alanine dimethylamide

Obtained from the previous product (Example 79(a) ) by a proceduresimilar to that described in Example 2, but using 10% palladium oncharcoal as catalyst, as an oil. Rf 0.10 (SS 7). LRMS: m/z 117.0 (M+1)⁺.

(c) N-Acryloyl-B-alanine dimethylamide

Obtained from the previous product (Example 79(b)) and acryloylchloride, by a procedure similar to that described in Example 75(a), asa solid, m.p. 79°-80.5° C. Rf 0.46 (SS 7). Found: C,55.42; H,8.29;N,16.04. C₈ H₁₄ N₂ O₂ ; 0.20 H₂ O requires C,55.28; H,8.35; N,16.12%.LRMS: m/z 171.4 (M+1)⁺.

(d)

The title compound was obtained from the previous product (Example79(c)). and the title compound of Example 33, by a procedure similar tothat described in Example 28(a), as a foam. Rf 0.16 (SS 7). [α]_(D) ²⁵+44° (c=0.1, CH₃ OH). Found: C,67.35; H,8.35; N,11.00. C₂₈ H₄₂ N₄ O₃ ;0.33 CH₂ Cl₂ requires C,67.74; H,8.45; N,11.03%. LRMS: m/z 483.2 (M+1)⁺.

EXAMPLE 803-[N-(3-Benzyloxycarbonyl-1-propyl)-2(R)-pyrrolidinylmethyl]-5-[2-(1-hydroxycyclopentyl)ethyl]-1H-indole

(a) Benzyl 4-bromobutanoate

80% Sodium hydride dispersion in oil (0.18 g, 5.9 mmol) was addedportionwise to a stirred solution of benzyl alcohol (0.64 g, 5.9 mmol)in anhydrous tetrahydrofuran (10 ml) under nitrogen. After a further 1hour at room temperature, the reaction mixture was cooled to -70° C. anda solution of 4-bromobutanoyl chloride (1.0 g, 5.4 mmol) in anhydroustetrahydrofuran (3 ml) added dropwise. After 0.5 hour, the cooling bathwas removed and the reaction mixture quenched at room temperature with5% aqueous ammonium chloride solution (20 ml) and then extracted withdichloromethane (3×20 ml). The combined extracts were washed withsaturated brine, dried (Na₂ SO₄) and evaporated under reduced pressure,then the residue was purified by column chromatography on silica gel,eluting with dichloromethane, to give the required ester as a gum. Rf0.60 (SS 16).

(b)

The title compound was obtained from the previous product (Example80(a)) and the title compound of Example 33, by a procedure similar tothat described in Example 24(A)(a), as a gum. Rf 0.50 (SS 7). [α]_(D) ²⁵+8° (c=0.1, CH₃ OH). Found: C,74.62; H,8.11; N,5.43. C₃₁ H₄₀ N₂ O₃ ;0.83 CH₂ Cl₂ ; 0.25 H₂ O requires C,74.63; H,8.19; N,5.60%.

EXAMPLE 815-[2-(1-Hydroxycyclopentyl)ethyl]-3-{N-[3-(N-methylcarbamoyl)-1)-1-propyl]-2(R)-pyrrolidinylmethyl}-1H-indole

(a)5-[2-(1-Hydroxycyclopentyl)ethyl]-3-[N-(3-carboxy-1-propyl)-2(R)-pyrrolidinylmethyl]-1H-indole

Obtained from the title compound of Example 80 by a procedure similar tothat described in Example 2, but using 10% palladium on charcoal ascatalyst, as a foam. Rf 0.15 (SS 7). [α]_(D) ²⁵ -49° (c=0.1, CH₃ OH).Found: C,66.41; H,8.43; N,6.38. C₂₄ H₃₄ N₂ O₃ ; 0.50 CH₂ Cl₂ requiresC,66.72; H,8.00; N,6.35%. LRMS: m/z 381.2 (M+1-H₂ O)⁺.

(b)

A solution of the previous product (Example 81(a) 200 mg, 0.5 mmol),methylamine hydrochloride (37 mg, 0.55 mmol), 1-hydroxybenzotriazole (68mg, 0.5 mmol), 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride(125 mg, 0.65 mmol) and N-methylmorphoiine (0.19 ml, 1.7 mmol) indichloromethane (10 ml) was stirred under nitrogen at 0°-5° C. for 1hour and then at room temperature for 24 hours. The reaction mixture wasagain cooled using an ice bath and further quantities of1-hydroxybenzotriazole (68 mg, 0.5 mmol),1-ethyl-3dimethylaminopropylcarbodiimide hydrochloride (100 mg, 0.52mmol) and N-methylmorpholine (0.2 ml) added. After a further 0.5 hour, afurther quantity of methylamine hydrochloride (100 mg, 1.5 mmol) wasadded, and stirring at 0°-5° C. continued for 2 hours and then at roomtemperature for a further 70 hours. The resulting reaction mixture waswashed with water and saturated brine, dried (Na₂ SO₄) and evaporatedunder reduced pressure, then the residue purified by columnchromatography on silica gel, eluting initially with dichloromethane andthen with a solvent gradient of 0.880 aqueousammonia:methanol:dichloromethane (0:10:90 to 1:10:90 to 2:20:80), toafford the title compound as a foam. Rf 0.15 (SS 7). [α]_(D) ²⁵ +22°(c=0.1, CH₃ OH).

Found: C,68.66; H,8.54; N,9.61. C₂₅ H₃₇ N₃ O₂ ; 0.17 CH₂ Cl₂ ; 0.75 H₂ Orequires C,68.81; H,8.91; N,9.58 %. LRMS: m/z 412.7 (M+1)⁺.

EXAMPLE 825-[2-(1-Hydroxycyclopentyl)ethyl]-3-{N-[4-(N-methylcarbamoyl)-1-butyl]-2(R)-pyrrolidinylmethyl}-1H-indole

(a) N-Methyl-5-bromopentanamide

Obtained from 5-bromopentanoic acid and methylamine hydrochloride, by aprocedure similar to that described in Example 81(b), as an oil. Rf 0.35(SS 17). Found: C,36.61; H,6.58; N,6.82. C₆ H₁₂ BrNo requires C,37.13;H,6.23; N,7.22%.

(b)

The title compound was obtained from the previous product (Example82(a)) and the title compound of Example 33, by a procedure similar tothat described in Example 24(A)(a), as a foam. Rf 0.15 (SS 7). [α]_(D)²⁵ +41° (c=0.1, CH₃ OH). Found: C,71.18; H,9.23; N,9.57. C₂₆ H₃₉ N₃ O₂ ;0.67 H₂ O requires C,71.35; H,9.29; N,9.60%. LRMS: m/z 425.8 (M)⁺.

EXAMPLE 835-[2-(1-Hydroxycyclopentyl)ethyl]-3-{N-[5-(N-methylcarbamoyl)-1-pentyl]-2(R)-pyrrolidinylmethyl}-1H-indole

(a) N-Methyl-6-iodohexanamide

Obtained from 6-iodohexanoic acid and methylamine hydrochloride, by aprocedure similar to that described in Example 81(b), as a foam. Rf 0.30(SS 17). Found: C,33.84; H,5.47; N,5.35. C₇ H₁₄ INO; 0.10 CH₃ CO₂ CH₂CH₃ requires C,33.67; H,5.65; N,5.31%. LRMS: m/z 256.1 (M+1)⁺.

(b)

The title compound was obtained from the previous product (Example83(a)) and the title compound of Example 33, by a procedure similar tothat described in Example 24(A)(a), as a foam. Rf 0.10 (SS 7). [α.sub.²⁵+32° (c=0.1, CH₃ OH). Found: C,71.31; H,9.82; N,9.24. C₂₇ H₄₁ N₃ O₂ ;0.75 H₂ O requires C,71.56; H,9.45; N,9.27%. LRMS: m/z 440.4 (M+1)⁺.

EXAMPLE 845-(3-Hydroxy-3-methyl-1-butyl]-3-{N-[5-(N-methylcarbamoyl)-1-pentyl]-2(R)-pyrrolidinylmethyl}-1H-indole

Obtained from the product of Example 83(a) and the title compound ofExample 29, by a procedure similar to that described in Example24(A)(a), as a foam. Rf 0.30 (SS 7). [α]_(D) ²⁵ +51° (c=0.1, CH₃ OH).Found: C,69.12; H,9.76; N,9.53. C₂₅ H₃₉ N₃ O₂ ; 0.10 CH₂ Cl₂ ; 0.75 H₂ Orequires C,69.21; H,9.42; N,9.65%. LRMS: m/z 414.6 (M+1)⁺.

EXAMPLE 855-[2-(1-Hydroxycyclopentyl)ethyl]-3-[N-(2-sulphamoylethyl)-2(R)-pyrrolidinylmethyl]-1H-indole

Obtained from the title compound of Example 33 and vinylsulphonamide bya procedure similar to that described in Example 28(a), but usingdimethylformamide as solvent, as a foam. Rf 0.40 (SS 7). [α]_(D) ²⁵ +49°(c=0.1, CH₃ OH). Found: C,61.38; H,8.16; N,9.60. C₂₂ H₃₃ N₃ O₃ S; 0.17CH₂ Cl₂ requires C,61.38; H,7.75; N,9.69%. LRMS: m/z 420.1 (M+1)⁺.

EXAMPLE 865-[2-(1-Hydroxycyclopentyl)ethyl]-3-{N-[2-(N-methylsulphamoyl)ethyl]-2(R)-pyrrolidinylmethyl}-1H-indole

Obtained from the title compound of Example 33 andN-methylvinylsulphonamide (WO-A-92/06973), by a procedure similar tothat described in Example 28(a), as a foam. Rf 0.49 (SS 7). [α]_(D) ²⁵+38° (c=0.1, CH₃ OH). Found: C,62.47; H,8.11, N,9.29. C₂₃ H₃₅ N₃ O₃ S;0.05 CH₂ Cl₂ ; 0.25 H₂ O requires C,62.57; H,8.11; N,9.49%. LRMS: m/z434.7 (M+1)⁺.

EXAMPLE 875-[2-(1-Hydroxycyclopentyl)ethyl]-3-{N-[2-(N,N,-dimethylsulphamoyl)ethyl]-2(R)-pyrrolidinylmethyl}-1H-indole

Obtained from the title compound of Example 33 andN,N-dimethylvinylsulphonamide (WO-A-92/06973), by a procedure similar tothat described in Example 28(a), as a solid, m.p. 118.5°-119.5° C. Rf0.91 (SS 7). [α]_(D) ²⁵ +31° (c=0.1, CH₃ OH). Found: C,64.03; H,8.57;N,9.30. C₂₄ H₃₇ N₃ O₃ S requires C,64.39; H,8.33; N,9.39%. LRMS: m/z448.3 (M+1)⁺.

EXAMPLE 883-[N-(2-Aminoethyl)-2(R)-pyrrolidinylmethyl]-5-[2-(1-hydroxycyclopentyl)ethyl]-1H-indole

(a)5-[2-(1-Hydroxycyclopentyl)ethyl]-3-[N-(2-phthalimidoethyl)-2(R)-pyrrolidinylmethyl]-1H-indole

Obtained from the title compound of Example 33 andN-(2-bromoethyl)phthalimide by a procedure similar to that described inExample 24(A)(a), but using anhydrous potassium carbonate as base andacetonitrile as solvent, as a foam. Rf 0.48 (SS 7). [α]_(D) ²⁵ +25°(c=0.1, CH₃ OH). Found: C,69.10; H,6.75; N,7.47. C₃₀ H₃₅ N₃ O₃ ; 0.50CH₂ Cl₂ ; 0.10 H₂ O requires C,69.12; H,6.88; N,7.93%. LRMS: m/z 486.3(M+1)⁺.

(b)

The title compound was obtained from the previous product (Example88(a)) and hydrazine hydrate, by a procedure similar to that describedin Example 47(b), as a foam. Rf 0.19 (SS 4). [α]_(D) ²⁵ +48° (c=0.1, CH₃OH). Found: C,72.42; H,9.07; N,11.14. C₂₂ H₃₃ N₃ O; 0.03 CH₂ Cl₂ ; 0.50H₂ O requires C,72.11; H,9.35; N,11.45%. LRMS: m/z 356.5 (M+1)⁺.

EXAMPLE 893-[N-(2-Acetamidoethyl)-2(R)-pyrrolidinylmethyl]-5-[2(1-hydroxycyclopentyl)ethyl]-1H-indole

Triethylamine (86 μl, 0.62 mmol) and then acetic acid anhydride (58 μl ,0.62 mmol) were added to a stirred solution of the title compound ofExample 88 (200 mg, 0.56 mmol) in dichloromethane (10 ml) at -40° C.under nitrogen. The cooling bath was removed and, after 2 hours, thereaction mixture was partitioned between dichloromethane and water. Theorganic phase was washed with water, dried (Na₂ SO₄) and evaporatedunder reduced pressure to give a foam which was purified by columnchromatography on silica gel, eluting initially with dichloromethane andthen with a solvent gradient of 0.880 aqueousammonia:methanol:dichloromethane (0:5:95 to 1:10:90), to yield the titlecompound (180 mg) as a foam. Rf 0.19 (SS 7). [α]_(D) ²⁵ +46° (c=0.1, CH₃OH). Found: C,70.59; H,8.94; N,10.40. C₂₄ H₃₅ N₃ O₂ ; 0.10 CH₂ Cl₂ ;0.50 H₂ O requires C,70.87; H,8.93; N,10.29%. LRMS: m/z 397.9 (M+1)⁺.

EXAMPLE 905-[2-(1-Hydroxycyclopentyl)ethyl]-3-[N-(2-methanesulphonamidoethyl)-2(R)-pyrrolidinylmethyl]-1H-indole

Obtained from the title compound of Example 88 by a procedure similar tothat described in Example 89, but using methanesulphonyl chloride as theelectrophile, an addition temperature of -78° C. and subsequent stirringat room temperature for 18 hours, as a foam. Found: C,59.88; H,7.87;N,9.51. C₂₃ H₃₅ N₃ O₃ S; 0.25 CH₂ Cl₂ ; 0.50 H₂ O requires C,60.19;H,7.92; N,9.06%. LRMS: m/z 433.7 (M+1)⁺.

EXAMPLE 915-[2-(1-Hydroxycyclopentyl)ethyl]-3-[N-(2-sulphamidoethyl)-2(R)-pyrrolidinylmethyl]-1H-indole

A stirred solution of the title compound of Example 88 (200 mg, 0.56mmol) and sulphamide (270 mg, 2.8 mmol) in 1,4-dioxane (5 ml), undernitrogen, was heated under reflux for 1.5 hours. The solvent was removedby evaporation under reduced pressure and the residue partitionedbetween dichloromethane and water. The organic phase was dried (Na₂ SO₄)and evaporated under reduced pressure to give an oil which was purifiedby column chromatography on silica gel, eluting initially withdichloromethane and then with a solvent gradient of 0.880 aqueousammonia:methanol:dichloromethane (0:1:99 to 1:10:90), to furnish thetitle compound as a foam. Rf 0.25 (SS 7). [α]_(D) ²⁵ +57° (c=0.1, CH₃OH). Found: C,60.43; H,7.91; N,11.75. C₂₂ H₃₄ N₄ O₃ S; 0.40 CH₃ CH₂ OHrequires C,60.44; H,8.09; N,12.37%. LRMS: m/z 435.4(M+1)⁺.

EXAMPLE 925-(3-Hydroxy-3,4-dimethyl-1-pentyl)-3-(2(R)-pyrrolidinylmethyl)-1H-indole

(a) 3,4-Dimethylpent-1-en-3-ol

Obtained by a procedure similar to that described in Example 5(a), using3-methylbutan-2-one as the appropriate ketone, as an oil. The crudeproduct was purified by column chromatography on silica gel, elutingwith n-pentane, to afford the required alcohol as a 1:1 mixture withn-pentane which was used as such in the next step. Rf 0.50 (SS 10).δ(CDCl₃): 0.82-1.00 (12H, m), 1.15-1.38 (9H, m), 1.65-1.90 (1H, m),5.08-5.25 (2H, dd), 5.88-5.98 (1H, dd).

(b)3-(N-Benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5(3-hydroxy-3,4-dimethyl-1-pent-1-enyl)-1H-indole

Obtained from the previous product (Example 92(a)) and the titlecompound of Preparation 1, by a procedure similar to that described inExample 1, as a foam. Rf 0.70 (SS 7). Found: C,74.96; H,7.48; N,6.01.C₂₈ H₃₄ N₂ O₃ ; 0.05 CH₂ Cl₂ requires C,74.73; H,7.62; N,6.21%.

(c)

The title compound was obtained from the previous product (Example92(b)) by a procedure similar to that described in Example 2, but using10% palladium on charcoal as catalyst, as a foam. Rf 0.10 (SS 7).[α]_(D) ²⁵ -19° (c=0.1, CH₃ OH). Found: C,73.66; H,9.52; N,8.32. C₂₀ H₃₀N₂ O; 0.10 CH₂ Cl₂ ; 0.25 H₂ O requires C,73.72; H,9.45; N,8.56%. LRMS:m/z 315.3 (M+1)⁺.

EXAMPLE 935-(3-Cyclopentyl-3-oxo-1-propyl)-3-(2(R)-pyrrolidinylmethyl)-1H-indole

(a) N-Cyclopentanecarbonyl-N,O-dimethylhydroxylamine

Oxalyl chloride (7.5 ml, 85 mmol) was added dropwise to a stirredsolution of cyclopentanecarboxylic acid (4.56 g, 40 mmol) anddimethylformamide (2 drops) in dichloromethane (20 ml) under nitrogen atroom temperature. After 2 hours, the reaction mixture was evaporatedunder reduced pressure and the residual oxalyl chloride removedazeotropically using dichloromethane. The resulting oil was dissolved indichloromethane (50 ml) and N,O-dimethylhydroxylamine (4.3 g, 44 mmol)added portionwise to the stirred solution. The resulting mixture wascooled using an ice bath, pyridine (7.1 ml, 88 mmol) added, the coolingbath removed and stirring continued for 18 hours. The reaction mixturewas then diluted with dichloromethane (50 ml), washed with 5% aqueouscitric acid solution (×2) and saturated brine, dried (Na₂ SO₄) andevaporated under reduced pressure. The residue was purified bychromatography on silica gel, eluting with a solvent gradient ofmethanol:dichloromethane (0:100 to 2:98), to furnish the required amideas an oil. Rf 0.50 (SS 18). Found: C,59.28; H,9.74; N,8.81. C₈ H₁₅ NO₂ ;0.25 H₂ O requires C,59.41; H,9.66; N,8.66%.

(b) Cyclopentyl vinyl ketone

Obtained (with dichloromethane as solrate) from the previous product(Example 93(a)) and vinylmagnesium bromide, using a procedure similar tothat described in Example 5(a), as an oil. Rf 0.60 (SS 16).

(c)3-(N-Benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-(3-cyclopentyl-1-prop-1-enyl)-1H-indole

Obtained from the previous product (Example 93(b)) and the titlecompound of Preparation 1, using a procedure similar to that describedin Example 1, as a foam. Rf 0.50 (SS 19). [α]_(D) ²⁵ -44° (c=0.1, CH₃OH). Found: C,75.18; H,7.06;.N,5.83. C₂₉ H₃₂ N₂ O₃ ; 0.10 CH₂ Cl₂requires C,75.15; H,6.98; N,6.02%. LRMS: m/z 457.2 (M+1)⁺.

(d)

The title compound was obtained. from the previous product (Example93(c)) by a procedure similar to that described in Example 2, but using10% palladium on charcoal as catalyst, as a foam. Rf 0.20 (SS 7). Found:C,74.65; H,8.40; N,8.20. C₂₁ H₂₈ N₂ O; 0.20 CH₂ Cl₂ requires C,74.57;H,8.38; N,8.21%. LRMS: m/z 325.2 (M+1)⁺.

EXAMPLE 945-(3-Cyclopentyl-3-hydroxy-1-propyl-3-(2(R)-pyrrolidinylmethyl)-1H-indole

The title compound was obtained from the title compound of Example 93,by a procedure similar to that described in Example 38, as a foam. Rf0.10 (SS 7). [α]_(D) ²⁵ -19° (c=0.1, CH₃ OH). Found: C,74.71; H,9.21;N,8.33. C₂₁ H₃₀ N₂ O; 0.67 H₂ O requires C,74.51; H,9.33; N,8.38%. LRMS:m/z 327.3 (M+1)⁺.

EXAMPLE 955-(3-Hydroxy-3-trifluoromethyl-1-butyl)-3-(2(R)-pyrrolidinylmethyl)-1H-indole

(a) 2-Trifluoromethylbut-3-en-2-ol

Obtained (with tetrahydrofuran as solvate) from 1,1,1-trifluoroacetoneand vinylmagnesium bromide, using a procedure similar to that describedin Example 5(a), as an oil (product:tetrahydrofuran (30:70)). δ(CDCl₃):1.42 (3H, s), 1.78-1.95 (4.7H, m), 2.42 (1H, s), 3.65-3.80 (4.7H, m),5.38 (1H, d), 5.55 (1H, d), 5.95-6.18 (1H, dd).

(b)3-N-(Benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5(3-hydroxy-3-trifluoromethyl-1-but-1-enyl)-1H-indole

Obtained from the previous product (Example 95(a)) and the titlecompound of Preparation 1, using a procedure similar to that describedin Example 1, as a foam. Rf 0.75 (SS 7). [α]_(D) ²⁵ -14° (c=0.1, CH₃OH). Found: C,64.36; H,5.65; N,5.59. C₂₆ H₂₇ F₃ N₂ O₃ ; 0.10 CH₂ Cl₂requires C,64.37; H,5.77; N,5.75%.

(c)

The title compound was obtained from the previous product (Example95(b)) by a procedure similar to that described in Example 2, but.using10% palladium on charcoal as catalyst, as a foam. Rf 0.08 (SS 7).[α]_(D) ²⁵ -24° (c=0.1, CH₃ OH). Found: C,61.46; H,6.48; N,7.83. C₁₈ H₂₃F₃ N₂ O; 0.10 CH₂ Cl₂ ; 0.25 H₂ O requires C,61.52; H,6.76; N,7.93%.LRMS: m/z 341.2 (M+1)⁺.

EXAMPLE 965-(3-Hydroxy-3-trifluoromethyl-1-but-1-enyl)-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole

Obtained from the product of Example 95(a) and5-bromo-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole (WO-A-92/06973),by a procedure similar to that described in Example 1, as a foam. Rf0.15 (SS 7). Found: C,60.50; H,6.61; N,7.61. C₁₉ H₂₃ F₃ N₂ O; 0.125 CH₂Cl₂ requires C,60.29; H,6.68; N,7.35%. LRMS: m/z 353.2 (M+1)⁺.

EXAMPLE 975-(3-Hydroxy-3-trifluoromethyl-1-butyl)-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole

Obtained from the title compound of Example 96 by a procedure similar tothat described in Example 2, but using 10% palladium on charcoal ascatalyst, as a foam. Rf 0.40 (SS 7). Found: C,59.55; H,6.86; N,7.10. C₁₉H₂₅ F₃ N₂ O; 0.17 CH₂ Cl₂ ; H₂ O requires C,59.55; H,7.13; N,7.25%.LRMS: m/z 355.0 (M+1)⁺.

EXAMPLE 985-(3-Hydroxy-3-trifluoromethyl-1-but-1-enyl)-3-{N-[2-(N-methylcarbamoyl)ethyl]-2(R)-pyrrolidinylmethyl}-1H-indole

Obtained from the products of Example 95(a) and Example 65(a), by aprocedure similar to that described in Example 1, as a foam. Rf 0.15 (SS7). Found: C,60.51; H,6.81; N,9.34. C₂₂ H₂₈ F₃ N₃ O₂ ; 0.10 CH₂ Cl₂ ;0.50 H₂ O requires C,60.19; H,6.67; N,9.53%. LRMS: m/z 424.5 (M+1)⁺.

EXAMPLE 995-(3-Hydroxy-3-trifluoromethyl-1-butyl)-3-{N-[2-(N-methylcarbamoyl)ethyl]2(R)-pyrrolidinylmethyl}-1H-indole

Obtained from the title compound of Example 98 by a procedure similar tothat described in Example 2, but using 10% palladium on charcoal ascatalyst, as a foam. Rf 0.45 (SS 7). [α]_(D) ²⁵ +39° (c=0.1, CH₃ OH).Found: C,59.07; H,7.16; N,9.21. C₂₂ H₃₀ F₃ N₃ O₂ ; 0.05 CH₂ Cl₂ ; H₂ Orequires C,59.15; H,7.22; N,9.39%. LRMS: m/z 426.4 (M+1)⁺.

EXAMPLE 1005-[2-(3-Hydroxy-3-tetrahydrofuranyl)ethenyl]-3-{N-[2-(N,N-dimethylcarbamoyl)ethyl]-2(R)-pyrrolidinylmethyl}-1H-indole

(a) 3-Hydroxy-3-vinyltetrahydrofuran

Obtained from tetrahydrofuran-3-one (J. Org. Chem., 1989, 54, 1249) andvinylmagnesium bromide, by a procedure similar to that described inExample 5(a), as an oil. Rf 0.45 (SS 7). δ(CDCl₃): 1.90 (1H, br s),1.92-2.20 (2H, m), 3.62-3.78 (2H, m), 3.92-4.10 (2H, m), 5.20 (1H, d),5.44 (1H, d), 5.95-6.08 (1H, dd). HRMS: m/z 114.068.

(b)

The title compound was obtained from the previous product (Example100(a)) and the product of Example 34(a), by a procedure similar to thatdescribed in Example 1, as a foam. Rf 0.26 (SS 7). [α]_(D) ²⁵ +33°(c=0.1, CH₃ OH). Found: C,64.18; H,7.92; N,9.06. C₂₄ H₃₃ N₃ O₃ ; 0.05CH₂ Cl₂ ; 0.10 H₂ O requires C,64.08; H,7.51; N,9.13%. LRMS: m/z 412.0(M+1)⁺.

EXAMPLE 1015-[2-(3-Hydroxy-3-tetrahydrofuranyl)ethyl]-3-{N-[2-(N,N-dimethylcarbamoyl)ethyl]-2(R)-pyrrolidinylmethyl}-1H-indole

Obtained from the title compound of Example 100 by a procedure similarto that described in Example 2, but using 10% palladium on charcoal ascatalyst, as a foam. Rf 0.16 (SS 7). [α]_(D) ²⁵ +42° (c=0.1, CH₃ OH).Found: C,67.20; H,9.18; N,9.41. C₂₄ H₃₅ N₃ O₃ ; 0.10 CH₃ CH₂ OH; 0.90 H₂O requires C,66.91;.H,8.67;. N,9.67%. LRMS: m/z 414.47 (M+1)⁺.

EXAMPLE 1025-(3-Hydroxy-3-methyl-1-butyl)-3-(N-methyl-4-piperidyl-1H-indole

Obtained from the title compound of Example 46 by a procedure similar tothat described in Example 2, but using 10% palladium on charcoal ascatalyst, as a solid, m.p. 144°-145° C. Rf 0.32 (SS 7). Found: C,74.57;H,9.61; N,8.98. C₁₉ H₂₈ N₂ O; 0.12 CH₃ CH₂ OH requires C,74.68; H,9.46;N,9.16%. LRMS: m/z 301.2 (M+1)⁺.

EXAMPLE 1035-[2-(1-Hydroxycyclopentl)ethyl]-3-[4-(1,2,5,6-tetrahvdropyridyl)]-1H-indole

(a) 5- [2-(1-Hydroxycyclopentyl)ethenyl]-1H-indole

Obtained from the product of Example 5(a) and 5-bromoindole, by aprocedure similar to that described in Example 1, as a solid. Rf 0.57(SS 7). Found: C,78.42; H,7.24; N,5.51. C₁₅ H₁₇ NO; 0.13 H₂ O requiresC,78.41; H,7.58; N,6.09%. LRMS: m/z 210.1 (M+1-H₂ O)⁺.

(b) 5-[2-(1-Hydroycyclopentyl)ethyl]-1H-indole

Obtained from the previous product (Example 103(a)) by a proceduresimilar to that described in Example 2, but using 10% palladium oncharcoal as catalyst and a 1:10 mixture of N,N-dimethylacetamide:ethanolas solvent, as a solid, m.p. 117°-118° C. Rf 0.67 (SS 7). Found:C,77.93; H,8.44; N,5.58. C₁₅ H₁₉ NO; 0.10 H₂ O requires C,77.95; H,8.37;N,6.06%. LRMS: m/z 212 (M+1-H₂ O)⁺.

(c)

Potassium hydroxide (53.9 mg, 0.96 mmol) was added to a stirred solutionof the previous product (Example 103(b); 200 mg, 0.87 mmol) and4-piperidone monohydrate hydrochloride (148 mg, 0.096 mmol) in methanol(10 ml) under nitrogen and the resulting mixture heated under reflux for48 hours. The cool reaction mixture was poured into water (50 ml) andthe resulting solid collected, washed with water and dried in vacuo. Thecrude product was purified by chromatography on silica gel, eluting witha solvent gradient of 0.880 aqueous ammonia:methanol:dichloromethane(0:8:25 to 0:5:8:25), to furnish the title compound (112 mg) as a solid,m.p. 168°-169° C. Found: C,75.66; H,8.34; N,8.57. C₂₀ H₂₆ N₂ O; 0.10 CH₂Cl₂ requires C,75.36; H,8.28; N,8.78%. LRMS: m/z 311.2 (M+1)⁺.

EXAMPLE 1043-[4-(1-Benzyl-1,2,5,6-tetrahydropyridyl)]-5-[2-(1-hydroxycyclopentyl)ethyl]-1H-indole

Obtained from the product of Example 103(b) and 1-benzyl-4-piperidone,by a procedure similar to that described in Example 103(c), as a solid.Rf 0.65 (SS 7). Found: C,78.87; H,7.78; N,6.85. C₂₇ H₃₂ N₂ O; 0.10 CH₂Cl₂ ; 0.17 H₂ O requires C,78.73; H,7.95; N,6.80%. LRMS: m/z 401.6(M+1)⁺.

EXAMPLE 105 5-[2-(1-Hydroxycyclopentyl)ethyl]-3-(4-piperidyl)-1H-indole

Obtained from the title compound of Example 104 by a procedure similarto that described in Example 2, but using 10% palladium on charcoal ascatalyst, as a solid, m.p. 190°-191° C. Found: C,71.26; H,8.72; N,8.04.C₂₀ h₂₈ N₂ O; 0.30 CH₂ Cl₂ requires C,71.22; H,8.53; N,8.29%. LRMS: m/z313.3 (M+1)⁺.

EXAMPLE 1063-[2-(N-Benzyl-N-methylamino)ethyl]-5-[2-(1-hydroxycyclopentyl)ethenyl]-1H-indole

(a) N-Benzyl-N-methyl-5-bromo-3-indolylglyoxylamide

Oxalyl chloride (2.24 ml, 25 mmol) was added dropwise to a stirredsolution of 5-bromoindole (5.0 g, 25 mmol) in anhydrous tetrahydrofuran(60 ml) under nitrogen at room temperature. After 2 hours the reactionmixture was ice-cooled and a solution of N-methylbenzylamine (10.8 g, 89mmol) in anhydrous tetrahydrofuran (15 ml) added dropwise, then theresulting mixture was stirred for a further 2 hours at 0°-5° C. andpartitioned between ethyl acetate and 2M hydrochloric acid. The organicphase was washed with 2M hydrochloric acid and then water, dried (Na₂SO₄) and evaporated under reduced pressure to give a solid which wastriturated with a 1:2 mixture of hexane:ether, washed with ether (×3)and dried in vacuo, to afford the required product (7.02 g) as a solid.Rf 0.60 (SS 7). Found: C,57.65; H,4.02; N,7.50. C₁₈ H₁₅ BrN₂ O₂ ; 0.33H₂ O requires C,57.30; H,4.16; N,7.42%.

(b) 3-[2-(N-Benzyl-N-methylamino)ethyl]-5-bromo-1H-indole

A solution of the previous product (Example 106(a); 7.0 g, 18 mmol) inanhydrous tetrahydrofuran (50 ml) was added dropwise, over 10 minutes,to a stirred suspension of lithium aluminium hydride (2.0 g, 53 mmol) inanhydrous tetrahydrofuran (50 ml) under nitrogen, then the resultingmixture heated under reflux for 4 hours, allowed to cool and stirred fora further 18 hours at room temperature. The reaction mixture wasice-cooled, carefully quenched by the sequential dropwise addition ofwater (2 ml), 4M aqueous sodium hydroxide solution (2 ml) and water (6ml), then filtered. The filtrate was evaporated under reduced pressureand the residue azeotroped with dichloromethane to give a product which,by spectral analysis (infra red and ¹ H NMR), was shown to containpartially reduced material.

Thus further treatment with lithium aluminium hydride (4.0 g, 106 mmol)in anhydrous tetrahydrofuran (50 ml) at reflux temperature for 18 hourswas effected and the resulting reaction mixture worked up as before.Purification of the residue by column chromatography on silica gel,eluting with a solvent gradient of ethanol: dichloromethane (0:100 to0.5:99.5 to 3:97), yielded the required product (2.67 g) as an oil.Found: C,64.51; H,5.85; N,8.26. C₁₈ H₁₉ BrN₂ ; 0.10 CH₂ Cl₂ requiresC,64.51; H,5.78; N,8.32%. LRMS: m/z 343.0 (⁷⁹ Br M+1)⁺ and 345.0 (⁸¹ BrM+1)⁺.

(c)

The title compound was obtained from the previous product (Example106(b)) and the product of Example 5(a), by a procedure similar to thatdescribed in Example 1, as a foam. Rf 0.64 (SS 7). Found: C,78.53;H,8.00; N,7.38. C₂₅ H₃₀ N₂ O; 0.10 CH₂ Cl₂ requires C,78.39; H,7.95;N,7.32%. LRMS: m/z 375.3 (M+1)⁺.

EXAMPLE 107 5-[2-(1-Hydroxycyclopentyl)ethyl]-3-[2-(N-methylamino)ethyl]-1H-indole

Obtained from the title compound of Example 106 by a procedure similarto that described in Example 2, but using 10% palladium on charcoal ascatalyst, as a foam. Rf 0.06 (SS 7). Found: C,71.90; H,8.88; N,9.15. C₁₈H₂₆ N₂ O; 0.08 CH₂ Cl₂ ; 0.50 H₂ O requires C,71.49; H,9.05; N,9.26%.LRMS: m/z 287.6 (M+1)⁺.

EXAMPLE 1083-(N-Benzyl-3-pyrrolidinyl)-5-[2-(1-hydroxycyclopentyl)ethenyl]-1H-indole

(a) 3-(N-Benzyl-3-succinimidyl)-5-bromo-1H-indole

A stirred mixture of 5-bromoindole (8.0 g, 41 mmol), N-benzylmaleimide(8.13 g, 45 mmol) and glacial acetic acid, under nitrogen, was heatedunder reflux for 48 hours and then evaporated under reduced pressure.Residual solvent was removed azeotropically using toluene (2×50 ml) andthen ethyl acetate (2×50 ml), then the residue was purified by columnchromatography on silica gel, eluting with a solvent gradient of ethylacetate:hexane (1:3 to 2:3), to furnish the required product (11.49 g)as a solid, m.p. 169°-170° C. Rf 0.04 (SS 5). Found: C,59.74; H,3.87;N,7.07. C₁₉ H₁₅ BrN₂ O₂ requires C,59.54; H,3.94; N,7.31%.

(b) 3-(N-Benzyl-3-pyrrolidinyl)-5-bromo-1H-indole

A solution of the previous product (Example 108(a); 3.80 g, 9.9 mmol) inanhydrous tetrahydrofuran (50 ml) was added dropwise to a stirredsuspension of lithium aluminium hydride (2.26 g, 59 mmol) in anhydroustetrahydrofuran (50 ml) under nitrogen and the resulting mixture heatedunder reflux for 22 hours. The ice-cooled reaction mixture wascautiously quenched by the sequential dropwise addition of water (2.26ml), 4M aqueous sodium hydroxide solution (2.26 ml) and more water (6.78ml), then filtered. The filtrate was evaporated under reduced pressure,then the residue azeotroped with dichloromethane and purified bychromatography on silica gel, eluting with a solvent gradient ofethanol:dichloromethane (0:100 to 4:96), to provide the required product(2.18 g) as a foam. Rf 0.44 (SS 7). LRMS: m/z 355.0 (⁷⁹ Br M+1)⁺ and357.0 (⁸¹ Br M+1)⁺.

(c)

The title compound was obtained from the previous product (Example108(b)) and the product of Example 5(a), by a procedure similar to thatdescribed in Example 1, as a foam. Rf 0.51 (SS 7). Found: C,79.08;H,7.71; N,6.97. C₂₆ H₃₀ N₂ O; 0.08.CH₂ Cl₂ requires C,79.41; H,7.72;N,7.12%. LRMS: m/z 387.0 (M+1)⁺.

EXAMPLE 1095-[2-(1-Hydroxycyclopentyl)ethyl]-3-(3-pyrrolidinyl)-1H-indole

The title compound was obtained from the title compound of Example 108using a procedure similar to that described in Example 2, but using 10%palladium on charcoal as catalyst, as a foam. Rf 0.04 (SS 7). Found:C,71.39; H,8.96; N,8.12. C₁₉ H₂₆ N₂ O; 0.50 CH₃ CH₂ OH; 0.10 H₂ Orequires C,70.90; H,9.09; N,8.67%. LRMS: m/z 299.1 (M+1)⁺.

PREPARATION 13-(N-Benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-bromo-1H-indole

3-(N-Benzyloxycarbonyl-2(R)-pyrrolidinylcarbonyl)-5-bromo-1H-indole(WO-A-92/06973; 0.67 g, 1.57 mmol) was dissolved in dry tetrahydrofuran(20 ml) and, at room temperature under nitrogen, lithium borohydride (2Msolution in tetrahydrofuran; 1.2 ml, 2.4 mmol) was added. The reactionmixture was stirred at room temperature for 3 hours, heated under refluxfor 16 hours, then allowed to cool to room temperature. 2M Hydrochloricacid (10 ml) was added dropwise and the reaction mixture thenpartitioned between ethyl acetate and water. The separated organic phasewas washed with saturated aqueous sodium bicarbonate solution (×2) andbrine (×1), dried (Na₂ SO₄), and evaporated under reduced pressure togive a colourless oil. Purification by column chromatography on silicagel, eluting with dichloromethane, gave the title compound as an oil(0.32 g). Rf 0.20 (SS 16). Found: C,59.94; H,5.07; N,6.58. C₂₁ H₂₁ BrN₂O₂ ; 0.10 CH₂ Cl₂ requires C,60.08; H,5.07; N,6.64%. δ(CDCl₃)--mixtureof rotamers: 1.63-1.90 (4H, m), 2.60-2.82 (1H, m), 3.10-3.28 (1H, m),3.30-3.54 (2H, m), 4.18 (1H, m), 5.15-5.25 (2H, m), 5.30 (0.2H, s, CH₂Cl₂), 6.90 and 6.95 (1H, 2×s), 7.05-7.50 (7H, m), 7.70 and 7.85 (1H,2×s), 8.25 (1H, br s).

PREPARATION 2 5-Bromo-3-(2(R)-pyrrolidinylmethyl)-1H-indole

The title compound was prepared by any of the following methods.

(A)

A mixture of the title compound of Preparation 1 (10.0 g, 24.2 mmol) anda solution of hydrogen bromide in glacial acetic acid (36% w/w; 17 ml)was stirred at about 0° C. for 1 hour, then the solvent removed underreduced pressure and the residue azeotroped with toluene. The resultingoil was partitioned between dichloromethane and 2M aqueous sodiumcarbonate solution, then the organic phase separated, combined with afurther dichloromethane extract of the aqueous phase, dried (Na₂ SO₄)and evaporated under reduced pressure. Purification of the crude productby column chromatography on silica gel, eluting with a solvent gradientof 0.880 aqueous ammonia:methanol: dichloromethane (0:5:95 to 2:5:95),gave the title compound as an oil (2.01 g). Rf 0.10 (SS 7). [α]_(D) ²⁵-9° (c=0.1, CH₃ OH). Found: C,54.75; H,5.41; N,9.63. C₁₃ H₁₅ BrN₂ ; 0.20CH₂ Cl₂ requires C,54.84; H,5.37; N,9.67%.

(B)

A solution of the title compound of Preparation 1 (5.0 g, 12.1 mmol) indichloromethane was added dropwise to a stirred mixture of borontrifluoride etherate (17.15 g, 14.9 ml, 12.1 mmol) and ethanethiol (21.4g, 25.5 ml, 344 mmol) at room temperature under nitrogen. After 68 hoursthe reaction mixture was poured into 10% aqueous sodium carbonatesolution, then extraction with ethyl acetate (3×400 ml) effected.Evaporation under reduced pressure of the dried (Na₂ SO₄), combinedextracts, followed by column chromatography on silica gel of the crudeproduct, eluting with 0.880 aqueous ammonia:methanol: dichloromethane(1:10:90), provided the title compound as a foam (2.10 g). Rf 0.10 (SS7). [α]_(D) ²⁵ -12° (c=0.1, CH₃ OH). Found: C,55.04; H,5.29; N,9.83. C₁₃H₁₅ BrN₂ ; 0.06 CH₂ Cl₂ requires C,55.10; H,5.35; N,9.83%.

(C)

A saturated solution of hydrogen chloride in methanol (20 ml) was addedto a stirred, ice-cooled solution of the title compound of Preparation 1(10.0 g, 24.2 mmol) in dichloromethane (20 ml) under nitrogen. After 1hour the ice bath was removed and the reaction mixture stirred at roomtemperature for 48 hours and then evaporated under reduced pressure. Theresidual oil was triturated with ether (2×20 ml), then partitionedbetween ether (50 ml) and water (50 ml). The aqueous phase was washedwith ether (2×75 ml), basified with solid sodium carbonate and extractedwith ethyl acetate (2×75 ml), then the combined extracts washed withsaturated brine, dried (Na₂ SO₄) and evaporated under reduced pressure.The residue was purified by column chromatography on silica gel, elutingwith a solvent gradient of 0.880 aqueousammonia:methanol:dichloromethane (0:0:100 to 0:10:90 to 1:10:90), toafford the title compound as a solid, m.p. 120°-123.5° C. Rf 0.15 (SS7). Found: C,55.06; H,5.33; N,9.59. C₁₃ H₁₅ BrN₂ ; 0.25 H₂ O requiresC,55.04; H,5.51; N,9.88%.

(D)

A stirred solution of the title compound of Preparation 1 (360 mg, 0.87mmol) and potassium hydroxide (1.0 g, 17.8 mmol) in ethanol (20 ml) washeated under reflux for 72 hours. The ethanol was removed by evaporationunder reduced pressure and replaced with n-butanol (20 ml), then theresulting mixture stirred under reflux for a further 48 hours andevaporated under reduced pressure. The residue was purified as in (C)above to provide the title compound (73 mg). Rf 0.10 (SS 7).

Biological Activity

The following Table illustrates the in vitro activities for a range ofthe compounds of the invention on dog isolated saphenous vein strip.EC₅₀ represents the concentration of compound which causes 50% of themaximum contraction effected by it.

                  TABLE                                                           ______________________________________                                                              RELATIVE POTENCY                                                              EC.sub.50 (compound)                                    EXAMPLE     EC.sub.50 (M)                                                                           EC.sub.50 (5-HT)                                        ______________________________________                                         1          4.0 × 10.sup.-7                                                                   7.7                                                     25          4.8 × 10.sup.-7                                                                   6.4                                                     29          6.7 × 10.sup.-7                                                                   9.0                                                     30          9.4 × 10.sup.-7                                                                   7.2                                                     37          1.3 × 10.sup.-7                                                                   1.3                                                     43          5.6 × 10.sup.-7                                                                   8.0                                                     48          3.0 × 10.sup.-7                                                                   3.2                                                     95          3.2 × 10.sup.-7                                                                   4.0                                                     101         7.0 × 10.sup.-7                                                                   10.0                                                    109         7.5 × 10.sup.-7                                                                   8.5                                                     ______________________________________                                    

Safety Profile

Several of the compounds of the invention have been tested in consciousanimals, for example Examples and 29, and showed no signs of adverseacute toxicity at doses of up to 1 mg/Kg i.v. in dog and up to 10 mg/Kgi.v. in mouse.

I claim:
 1. A compound of formula (I): ##STR31## or a pharmaceuticallyacceptable salt thereof, or a pharmaceutically acceptable solvate ofeither entity, wherein R¹ is ##STR32## or CH₂ CH₂ NR³ R⁴ (E); R² is R⁵R⁶ C(OH)A or R⁷ COA; R³ is H; C₁ -C₆ alkyl; (R⁸ CO) C₁ -C₃ alkylene; (R⁹O₂ C) C₁ -C₃ alkylene; (R¹⁰ R¹¹ NOC) C₁ -C₆ alkylene; (R¹⁰ R¹¹ NO₂ S) C₁-C₃ alkylene; [R⁸ S(O)_(m) ]C₁ -C₃ alkylene; (R¹² O) C₂ -C₄ alkylene;(R¹³ NH) C₂ -C₄ alkylene; (C₃ -C₇ cycloalkyl) C₁ -C₃ alkylene; (aryl) C₁-C₃ alkylene; (heteroaryl) C₁ -C₃ alkylene; C₃ -C₇ cycloalkyl optionallysubstituted with HO; C₃ -C₆ alkenyl optionally substituted with aryl; C₅-C₇ cycloalkenyl; or C₃ -C₆ alkynyl;R⁴ is H or C₁ -C₆ alkyl; R⁵ and R⁶are each independently selected from H; C₁ -C₆ alkyl; C₁ -C₄perfluoroalkyl; and C₃ -C₇ cycloalkyl; or, together with the carbon atomto which they are attached, form a 3- to 7-membered carbocyclic ringwhich optionally incorporates a double bond or a heteroatom linkageselected from O, S(O)_(m), NH, N(C₁ -C₄ alkyl), and N(C₁ -C₅ alkanoyl);R⁷ and R⁸ are each independently selected from C₁ -C₆ alkyl; (C₃ -C₇cycloalkyl) C₁ -C₃ alkylene; (aryl) C₁ -C₃ alkylene; C₃ -C₇ cycloalkyl;and aryl; R⁹ is C₁ -C₆ alkyl; (C₃ -C₇ cycloalkyl ) C₁ -C₃ alkylene;(aryl) C₁ -C₃ alkylene; or C₃ -C₇ cycloalkyl; R¹⁰ and R¹¹ are eachindependently selected from H; C₁ -C₆ alkyl; (R¹⁴ R¹⁵ NOC) C₁ -C₃alkylene; (R¹⁶ O) C₂ -C₄ alkylene; (C₃ -C₇ cycloalkyl) C₁ -C₃ alkylene;(aryl) C₁ -C₃ alkylene; and C₃ -C₇ cycloalkyl; or, together with thenitrogen atom to which they are attached, form a 4- to 7-memberedheterocyclic ring which optionally incorporates a further heteroatomlinkage selected from O, S(O)_(m), NH, N(C₁ -C₄ alkyl), and N(C₁ -C₅alkanoyl); R¹² is H; C₁ -C₆ alkyl; (C₃ -C₇ cycloalkyl) C₁ -C₃ alkylene;(aryl) C₁ -C₃ alkylene; C₃ -C₇ cycloalkyl; or aryl; R¹³ is H; C₁ -C₅alkanoyl; (C₁ -C₄ alkyl)SO₂ ; or H₂ NSO₂ ; R¹⁴ and R¹⁵ are eachindependently selected from H or C₁ -C₄ alkyl; R¹⁶ is H; C₁ -C₄ alkyl;or benzyl; A is a direct link; C₁ -C₆ alkylene optionally branched withC₁ -C₄ alkyl; or C₂ -C₆ alkenylene optionally branched with C₁ -C₄alkyl; k and m are each independently selected from 0, 1 and 2;and thebroken line indicates an optional carbon-carbon single bond; with theproviso that, for a compound of formula (IE) wherein R² is R⁷ COA and Ais a direct link, R⁷ is not (a) methyl, ethyl, phenyl or 4-chlorophenylwhen both R³ and R⁴ are H; (b) methyl when both R³ and R⁴ are methyl; or(c) phenyl when both R³ and R⁴ are ethyl, or when either of R³ and R⁴ isethyl or butyl and the other is H.
 2. A compound according to claim 1 offormula (IA) wherein R² is R⁵ R⁶ C(OH)A or R⁷ COA; R³ is H; C₁ -C₄alkyl; (benzylO₂ C) C₁ -C₃ alkylene; (R¹⁰ R¹¹ NOC) C₁ -C₆ alkylene; (R¹⁰R¹¹ NO₂ S) C₁ -C₃ alkylene; (R⁸ SO₂) C₁ -C₃ alkylene; (R¹² O ) C₂ -C₄alkylene; (R¹³ NH) C₂ -C₄ alkylene; (C₄ -C₆ cycloalkyl) C₁ -C₃ alkylene;or (pyridyl) C₁ -C₃ alkylene; R⁵ and R⁶ are each independently selectedfrom H; C₁ -C₄ alkyl; CF₃ ; and cyclopentyl; or, together with thecarbon atom to which they are attached, form a 4- to 6-memberedcarbocyclic ring which optionally incorporates an oxygen atom linkage;R⁷ is C₁ -C₄ alkyl or C₄ -C₆ cycloalkyl; R⁸ is C₁ -C₄ alkyl; R¹⁰ and R¹¹are each independently selected from H; C₁ -C₄ alkyl; (R¹⁴ R¹⁵ NOC) C₁-C₃ alkylene; and (R¹⁶ O) C₂ -C₄ alkylene; or, together with thenitrogen atom to which they are attached, form a 5- to 6-memberedheterocyclic ring which optionally incorporates an oxygen atom linkage;R¹² is H; C₁ -C₄ alkyl; or benzyl; A is a direct link; C₁ -C₄ alkylene;or C₂ -C₄ alkenylene; k is 1; and R¹³, R¹⁴, R¹⁵ and R¹⁶ are aspreviously defined for formula (IA); of formula (IB) wherein R² is R⁵ R⁶C(OH)A; R³ is H or benzyl; R⁵ and R⁶ together with the carbon atom towhich they are attached form a 4- to 6-membered carbocyclic ring; A isethylene or vinyl; and the broken line is absent; of formula (IC)wherein R² is R⁵ R⁶ C(OH)A or R⁷ COA; R³ is H, C₁ -C₄ alkyl or benzyl;R⁵ and R⁶ are each independently selected from H and C₁ -C₄ alkyl; or,together with the carbon atom to which they are attached, form a 4- to6-membered carbocyclic ring; R⁷ is C₁ -C₄ alkyl; A is a direct link;ethylene or vinyl; and the broken line indicates an optionalcarbon-carbon single bond; .and of formula (IE): wherein R² is R⁵ R⁶C(OH)A; R³ and R⁴ are each independently selected from H, C₁ -C₄ alkyland benzyl; R⁵ and R⁶ are each C₁ -C₄ alkyl or, together with the carbonatom to which they are attached, form a 4- to 6-membered carbocyclicring; and A is ethylene or vinyl.
 3. A compound according to claim 2 offormula (IA) wherein R² is R⁵ R⁶ C(OH)A or R⁷ COA; R³ is H; C₁ -C₃alkyl; (R¹⁰ R¹¹ NOC) C₁ -C₅ alkylene; CH₃ NHO₂ SCH₂ CH₂ ; CH₃ OCH₂ CH₂ ;or (cyclopropyl)CH₂ ; R⁵ is methyl, R⁶ is H, methyl, ethyl or CF₃, or R⁵and R⁶ together with the carbon atom to which they are attached, form acyclobutyl, cyclopentyl or 3-tetrahydrofuranyl ring; R⁷ is methyl; R¹⁰and R¹¹ are each independently selected from H; methyl; (CH₃)₂ NOCCH₂ ;(CH₃)₂ NOCCH₂ CH₂ ; HOCH₂ CH₂ ; and CH₃ OCH₂ CH₂ ; and A is ethylene,propylene or vinyl; of formula (IC) wherein R² is R⁵ R⁶ C(OH)A; R³ is Hor methyl; R⁵ is methyl, R⁶ is H or methyl, or R⁵ and R⁶ together withthe carbon atom to which they are attached form a cyclopentyl ring; A isethylene or vinyl; and the broken line indicates an optionalcarbon-carbon single bond; and of formula (IE) wherein R² is R⁵ R⁶C(OH)CH₂ CH₂ ; R³ is methyl; R⁴ is H; and R⁵ and R⁶ together with thecarbon atom to which they are attached form a cyclopentyl ring.
 4. Acompound according to claim 3 of formula (IA) wherein R² is R⁵ R⁶C(OH)A; R³ is H; methyl; 2-propyl; CH₃ NHOCCH₂ CH₂ ; (CH₃)₂ NOCCH₂ CH₂ ;CH₃ NHOCCH₂ CH₂ CH₂ CH₂ ; CH₃ NHOCCH₂ CH₂ CH₂ CH₂ CH₂ ; HOCH₂ CH₂NHOCCH₂ CH₂ ; CH₃ OCH₂ CH₂ or (cyclopropyl)CH₂ ; R⁵ is methyl, R⁶ is H,methyl or CF₃, or R⁵ and R⁶ together with the carbon atom to which theyare attached form a cyclobutyl or cyclopentyl ring; and A is ethylene orvinyl; and of formula (IC) wherein R² is CH₃ CH(OH)CH₂ CH₂ ; R³ ismethyl; and the broken line is absent.
 5. A compound according to claim1 of formula (IA) wherein the preferred stereoisomer has the 2 (R)-configuration of formula (IA'): ##STR33## wherein R², R³ and k are aspreviously defined in said claims.
 6. A compound according to claim 5wherein the compound of formula (IA') is selectedfrom5-(3-hydroxy-1-butyl)-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole;3-(N-cyclopropylmethyl-2(R)-pyrrolidinylmethyl)-5-(3-hydroxy-3-methyl-1-butyl)-1H-indole;5-[2-(1-hydroxycyclopentyl)ethyl]-3-(2(R)-pyrrolidinylmethyl)-1H-indole;5-[2-(1-hydroxycyclopentyl)ethyl]-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole;5-[2-(1-hydroxycyclopentyl)ethyl]-3-{N-[2-(N-methylcarbamoyl)ethyl]-2(R)-pyrrolidinylmethyl}-1H-indole;and5-[2-(1-hydroxycyclopentyl)ethyl]-3-{N-[2-(N,N-dimethylcarbamoyl)ethyl]-2(R)-pyrrolidinylmethyl}-1H-indole.7. A pharmaceutical composition for treating a condition selected frommigraine, cluster headache, chronic paroxysmal hemicrania or headacheassociated with a vascular disorder, depression, anxiety, an eatingdisorder, obesity, drug abuse, and emesis comprising an amount of acompound according to claim 1 effective in treating such a conditiontogether with a pharmaceutically acceptable diluent or carrier.
 8. Amethod of treating a human being for a condition selected from migraine,cluster headache, chronic paroxysmal hemicrania or headache associatedwith a vascular disorder, depression, anxiety, an eating disorder,obesity, drug abuse or emesis, which comprises treating said human beingwith an effective amount of a compound according to claim
 1. 9. A methodof treating a human being for medical condition for which a selectiveagonist of 5-HT₁ -like receptors is indicated, which comprises treatingsaid human being with an effective amount of a compound according toclaim 1.